Hppars activators

ABSTRACT

Compounds of formula (1) or a pharmaceutically acceptable salt, solvate, acid isostere, or hydrolyzable ester thereof, are disclosed. Methods of making and using the compounds are also disclosed. In particular methods for treating diseases or conditions associated with one or more of human PPAR alpha, gamma, or delta (“hPPARs”) comprising administration of a therapeutically effective amount of a compound of formula (1), are disclosed.

The present invention relates to certain novel compounds. In particular,the present invention relates to compounds that activate humanperoxisome proliferator activated receptors (“hPPARs”). The presentinvention also relates to method for preparing the compounds, their usein medicine, pharmaceutical compositions containing them and methods forthe prevention or treatment of PPAR mediated diseases or conditions.

Several independent risk factors have been associated withcardiovascular disease. These include hypertension, increased fibrinogenlevels, high levels of triglycerides, elevated LDL cholesterol, elevatedtotal cholesterol, and low levels of HDL cholesterol. HMG CoA reductaseinhibitors (“statins”) are useful for treating conditions characterizedby high LDL-c levels. It has been shown that lowering LDL-c is notsufficient for reducing the risk of cardiovascular disease in somepatients, particularly those with normal LDL-c levels. This populationpool is identified by the independent risk factor of low HDL-c. Theincreased risk of cardiovascular disease associated with low HDL-clevels has not yet been successfully addressed by drug therapy (i.e.currently there are no drugs on the market that are useful for raisingHDL-c). (Bisgaier, C. L.; Pape, M. E. Curr. Pharm. Des. 1998, 4, 53-70).

Syndrome X (including metabolic syndrome) is loosely defined as acollection of abnormalities including hyperinsulemia, obesity, elevatedlevels of triglycerides, uric acid, fibrinogen, small dense LDLparticles, and plasminogen activator inhibitor 1 (PAI-1), and decreasedlevels of HDL-c.

NIDDM is described as insulin resistance which in turn causes anomalousglucose output and a decrease in glucose uptake by skeletal muscle.These factors eventually lead to impaired glucose tolerance (IGT) andhyperinsulinemia.

Peroxisome Proliferator Activated Receptors (PPARs) are orphan receptorsbelonging to the steroid/retinoid receptor superfamily ofligand-activated transcription factors. See, for example Willson T. M.and Wahli, W., Curr. Opin. Chem. Biol. (1997) Vol 1 pp 235-241 andWillson T. M. et. al., J. Med. Chem. (2000) Vol 43 p 527-549. Thebinding of agonist ligands to the receptor results in changes in theexpression level of mRNAs encoded by PPAR target genes.

Three mammalian Peroxisome Proliferator-Activated Receptors have beenisolated and termed PPAR-alpha, PPAR-gamma, and PPAR-delta (also knownas NUC1 or PPAR-beta). These PPARs regulate expression of target genesby binding to DNA sequence elements, termed PPAR response elements(PPRE). To date, PPRE's have been identified in the enhancers of anumber of genes encoding proteins that regulate lipid metabolismsuggesting that PPARs play a pivotal role in the adipogenic signalingcascade and lipid homeostasis (H. Keller and W. Wahli, Trends Endoodn.Met. 291-296, 4 (1993)).

It has been reported that thiazolidinediones are potent and selectiveactivators of PPAR-gamma and bind directly to the PPAR-gamma receptor(J. M. Lehmann et. al., J. Biol. Chem. 12953-12956, 270 (1995)),providing evidence that PPAR-gamma is a possible target for thetherapeutic actions of the thiazolidinediones.

Activators of the nuclear receptor PPARγ, for example troglitazone, havebeen shown in the clinic to enhance insulin-action, reduce serum glucoseand have small but significant effects on reducing serum triglyceridelevels in patients with Type 2 diabetes. See, for example, D. E. Kellyet al., Curr. Opin. Endocrinol. Diabetes, 90-96, 5 (2), (1998); M. D.Johnson et al., Ann. Pharmacother., 337-348, 32 (3), (1997); and M.Leutenegger et al., Curr. Ther. Res., 403-416, 58 (7), (1997).

The mechanism for this triglyceride lowering effect appears to bepredominantly increased clearance of very low density lipoproteins(VLDL) through induction of lipoprotein lipase (LPL) gene expression.See, for example, B. Staels et al., Arterioscler. Thromb., Vasc. Biol.,1756-1764, 17 (9), (1997).

Fibrates are a class of drugs which may lower serum triglycerides20-50%, lower LDLc 10-15%, shift the LDL particle size from the moreatherogenic small dense to normal dense LDL, and increase HDLc 10-15%.Experimental evidence indicates that the effects of fibrates on serumlipids are mediated through activation of PPARα. See, for example, B.Staels et al., Curr. Pharm. Des., 1-14, 3 (1), (1997). Activation ofPPARα results in transcription of enzymes that increase fatty acidcatabolism and decrease de-novo fatty acid synthesis in the liverresulting in decreased triglyceride synthesis and VLDLproduction/secretion. In addition, PPARα activation decreases productionof apoC-III. Reduction in apoC-III, an inhibitor of LPL activity,increases clearance of VLDL. See, for example, J. Auwerx et al.,Atherosclerosis, (Shannon, Irel.), S29-S37, 124 (Suppl), (1996).

Certain compounds that activate or otherwise interact with one or moreof the PPARs have been implicated in the regulation of triglyceride andcholesterol levels in animal models. See, for example, U.S. Pat. No.5,847,008 (Doebber et al.) and U.S. Pat. No. 5,859,051 (Adams et al.)and PCT publications WO 97/28149 (Leibowitz et al.) and WO99/04815(Shimokawa et al.). In a recent report (Berger et al., J. Biol. Chem.1999), vol. 274, pp. 6718-6725) it was stated that PPARδ activation doesnot appear to modulate glucose or triglyceride levels.

In one aspect, the present invention provides compounds of formula (1)and pharmaceutically acceptable salts, solvates, acid isosteres, andhydrolyzable esters thereof;

wherein

R¹ and R² are independently hydrogen, F, CF₃, C₁₋₃alkyl, or R¹ and R²may together with the carbon atom to which they are attached form a 3 to6-membered cycloakyl ring;

R⁴ and R⁵ are independently hydrogen, C₁₋₆alkyl, perfluoroC₁₋₆alkyl,—OC₁₋₃alkyl, perfluoroOC₁₋₆alkyl, halogen, or cyano;

R⁷and R⁸ are independently H, F, CF₃, or C₁₋₃alkyl, and the carbon towhich R⁷ and R⁸ are bonded is attached to the benzene ring either metaor para to the depicted oxygen;

n is 1 or 2;

y is 1 or 2;

R⁶ is phenyl or a 5- or 6-membered heteroaryl group, where the phenyl orheteroaryl group is optionally substituted with 1, 2, or 3 moietiesselected from the group consisting of C₁₋₆alkyl, halogen,perfluoroC₁₋₃alkyl, OC₁₋₃alkyl, perfluoroOC₁₋₃alkyl, SC₁₋₃alkyl,SO₂C₁₋₃alkyl, SO₂C₁₋₃perfluoroalkyl, SOC₁₋₃perfluoroalkyl, SOC₁₋₃alkyl,perfluoroSC₁₋₃alkyl, CN, phenyl (optionally substituted with one or twogroups selected from halogen, C₁₋₃alkyl, OC₁₋₃alkyl, acetyl, CN, andperfluoroC₁₋₃alkyl), and 5- or 6-membered heteroaryl (optionallysubstituted with one group selected from C₁₋₃alkyl, C₃₋₆cycloalkyl,perfluoroC₁₋₃alkyl, NHC₁₋₃alkyl, and N(C₁₋₃alkyl)₂); and

R³ is a 5- or 6-membered heteroaryl group optionally substituted by 1 or2 moieties selected from the group consisting of halogen, C₁₋₆alkyl,perfluoroC₁₋₆alkyl, OC₁₋₃alkyl, phenyl (optionally substituted with oneor two moieties selected from C₁₋₃alkyl, halogen, OC₁₋₃alkyl, acetyl,CN, OperfluoroC₁₋₃alkyl, and perfluoroC₁₋₃alkyl), 5- or 6-memberedheteroaryl (optionally substituted with one or two moieties selectedfrom C₁₋₃alkyl, halogen, OC₁₋₃alkyl, acetyl, CN, andperfluoroC₁₋₃alkyl), hydroxyC₁₋₃alkyl, C₃₋₇cycloalkyl, cyanoC₁₋₃alkyl,acetyl, nitro, N(CH₃)₂, NHR²¹ (where R²¹ is C₁₋₃alkyl, —C(O)C₁₋₃alkyl,—C(O)OC₁₋₃alkyl, or SO₂CH₃), piperidin-4-yl (substituted at nitrogenwith a moiety selected from C₁₋₅alkyl, benzyl, acetyl, C(O)OC₁₋₅alkyl,C(O)Obenzyl, C(O)NH₂, C(O)NHC₁₋₃alkyl, SO₂CH₃),4-(4-fluorophenyl)piperazin-1-ylmethyl, morpholin-4-ylmethyl,tetrahydrofuran-3-yl, or two adjacent carbon atoms in the heteroarylcould be substituted to form a benzene ring thus forming a fused bicycleand wherein the resulting benzene ring is optionally substituted withone or two moieties selected from C₁₋₃alkyl, halogen, andperfluoroC₁₋₃alkyl.

In another aspect, the present invention discloses a method forprevention or treatment of a disease or condition mediated by one ormore human PPAR alpha, gamma or delta (“hPPARs”) comprisingadministration of a therapeutically effective amount of a compound ofthis invention. hPPAR mediated diseases or conditions includedyslipidemia including associated diabetic dyslipidemia and mixeddyslipidemia, syndrome X (as defined in this application this embracesmetabolic syndrome), heart failure, hypercholesteremia, cardiovasculardisease including atherosclerosis, arteriosclerosis, andhypertriglyceridemia, type II diabetes mellitus, type I diabetes,insulin resistance, hyperlipidemia, inflammation, epithelialhyperproliferative diseases including eczema and psoriasis andconditions associated with the lung and gut and regulation of appetiteand food intake in subjects suffering from disorders such as obesity,anorexia bulimia, and anorexia nervosa. In particular, the compounds ofthis invention are useful in the treatment and prevention of diabetesand cardiovascular diseases and conditions including atherosclerosis,arteriosclerosis, hypertriglyceridemia, and mixed dyslipidaemia.

In another aspect, the present invention provides pharmaceuticalcompositions comprising a compound of the invention, preferably inassociation with a pharmaceutically acceptable diluent or carrier.

In another aspect, the present invention provides a compound of theinvention for use in therapy, and in particular, in human medicine.

In another aspect, the present invention provides the use of a compoundof the invention for the manufacture of a medicament for the treatmentof a hPPAR mediated disease or condition.

As used herein, “a compound of the invention” means a compound offormula (1) or a pharmaceutically acceptable salts, solvates, acidisosteres, and hydrolyzable esters thereof.

As used herein an “acid isostere thereof” means that the depicted CO₂Hgroup in formula (1) may be replaced with a group that is generallyrecognized as being functionally equivalent to a carboxylic acid group.The preferred acid isostere is tetrazole.

As used herein “alkyl” and terms containing alkyl such as“perfluooroalkyl” mean straight or branched unless otherwise indicated.

Preferably R¹ and R² are independently hydrogen or C₁₋₃alkyl. Morepreferably R¹ and R² are both hydrogen or both methyl.

Preferably R⁴ and R⁵ are independently hydrogen, C₁₋₃alkyl,perfluoroC₁₋₃alkyl, —OC₁₋₃alkyl, perfluoroOC₁₋₃alkyl, halogen, or cyano.Most preferably at least one of R⁴ and R⁵ are hydrogen, and when one ofR⁴ and R⁵ is hydrogen and the other is not then the one that is nothydrogen is preferably ortho to the depicted oxygen.

Preferably R⁷ and R³ are independently hydrogen or methyl. Morepreferably R⁷ and R⁸ are both hydrogen or both methyl.

Preferably y is 1.

Preferably R⁸ is phenyl. More preferably R⁶ is phenyl optionallysubstituted with 1 or 2 moieties selected from the group consisting ofF, Cl, CF₃, OCF₃, 5-membered nitrogen-containing heteroaryl (optionallysubstituted with one group selected from C₁₋₃alkyl, C₃₋₆cycloalkyl,perfluoroC₁₋₃alkyl, NHC₁₋₃alkyl, and N(C₁₋₃alkyl)₂).

Preferably the heteroaryl group in R³ is selected from the groupconsisting of pyrimidine, pyridine, pyridazine, pyrazine,1,2,4-oxadiazole, oxazole, and thiazole; and is optionally substitutedby a moiety selected from the group consisting of halogen, C₁₋₆alkyl,perfluoroC₁₋₆alkyl, phenyl (optionally substituted with one or twomoieties selected from C₁₋₃alkyl, halogen, OC₁₋₃alkyl, acetyl, CN, andperfluoroC₁₋₃alkyl), 5- or 6-membered heteroaryl (optionally substitutedwith one or two moieties selected from C₁₋₃alkyl, halogen, OC₁₋₃alkyl,acetyl, CN, and perfluoroC₁₋₃alkyl), hydroxyC₁₋₃alkyl, andC₃₋₇cycloalkyl, or R³ may be substituted to form a fused bicycleselected from benzoxazole and benzothiazole. More preferably theheteroaryl group in R³ is a thiazole, a pyrimidine, or a pyridine; andis optionally substituted by a moiety selected from the group consistingof halogen, C₁₋₆alkyl, perfluoroC₁₋₆alkyl, phenyl (optionallysubstituted with one or two moieties selected from C₁₋₃alkyl, halogen,OC₁₋₃alkyl, acetyl, CN, and perfluoroC₁₋₃alkyl), 5- or 6-memberedheteroaryl, hydroxyC₁₋₃alkyl, and C₃₋₇cycloalkyl.

Preferably, the compounds of formula (1) are hPPAR agonists. The hPPARagonists of formula (1) may be agonists of only one type (“selectiveagonists”), agonists for two PPAR subtypes (“dual agonists”), oragonists for all three subtypes (“pan agonists”). As used herein, by“agonist”, or “activating compound”, or “activator”, or the like, ismeant those compounds which have a pKi of at least 6.0 preferably atleast 7.0 to the relevant PPAR, for example hPPARδ in the binding assaydescribed below, and which achieve at least 50% activation of therelevant PPAR relative to the appropriate indicated positive control inthe transfection assay described below at concentrations of 10⁻⁵ M orless. More preferably, the compounds of this invention achieve 50%activation of at least one human PPAR in the relevant transfection assayat concentrations of 10⁻⁶ M or less. More preferably the compounds ofthe invention achieve 50% activation of at least one human PPAR in therelevant transfection assay at concentrations of 10⁻⁷ M or less.

It will also be appreciated by those skilled in the art that thecompounds of the present invention may also be utilized in the form of apharmaceutically acceptable salt or solvate thereof. The physiologicallyacceptable salts of the compounds of formula (1) include conventionalsalts formed from pharmaceutically acceptable inorganic or organic acidsor bases as well as quaternary ammonium acid addition salts. Morespecific examples of suitable acid salts include hydrochloric,hydrobromic, sulfuric, phosphoric, nitric, perchloric, fumaric, acetic,propionic, succinic, glycolic, formic, lactic, maleic, tartaric, citric,palmoic, malonic, hydroxymaleic, phenylacetic, glutamic, benzoic,salicylic, fumaric, toluenesulfonic, methanesulfonic,naphthalene-2-sulfonic, benzenesulfonic hydroxynaphthoic, hydroiodic,malic, steroic, tannic and the like. Other acids such as oxalic, whilenot in themselves pharmaceutically acceptable, may be useful in thepreparation of salts useful as intermediates in obtaining the compoundsof the invention and their pharmaceutically acceptable salts. Morespecific examples of suitable basic salts include sodium, lithium,potassium, magnesium, aluminium, calcium, zinc,N,N′-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine,ethylenediamine, N-methylglucamine and procaine salts. Those skilled inthe art of organic chemistry will appreciate that many organic compoundscan form complexes with solvents in which they are reacted or from whichthey are precipitated or crystallized. These complexes are known as“solvents”. For example, a complex with water is known as a “hydrate”.Solvates of the compound of formula (1) are within the scope of theinvention. References hereinafter to a compound according to theinvention include both compounds of formula (1) and theirpharmaceutically acceptable salts and solvates.

Those skilled in the art will recognize that stereocenters exist incompounds of formula (1). Accordingly, the present invention includesall possible stereoisomers and geometric isomers of formula (1) andincludes not only racemic compounds but also the optically activeisomers as well. When a compound of formula (1) is desired as a singleenantiomer, it may be obtained either by resolution of the final productor by stereospecific synthesis from either isomerically pure startingmaterial or any convenient intermediate. Resolution of the finalproduct, an intermediate or a starting material may be effected by anysuitable method known in the art. See, for example, Stereochemistry ofCarbon Compounds by E. L. Eliel (McGraw Hill, 1962) and Tables ofResolving Agents by S. H. Wilen. Additionally, in situations wheretautomers of the compounds of formula (1) are possible, the presentinvention is intended to include all tautomeric forms of the compounds.

The compounds of the invention and their pharmaceutically acceptablederivatives are conveniently administered in the form of pharmaceuticalcompositions. Such compositions may conveniently be presented for use inconventional manner in admixture with one or more physiologicallyacceptable carriers or excipients.

While it is possible that compounds of the present invention may betherapeutically administered as the raw chemical, it is preferable topresent the active ingredient as a pharmaceutical formulation. Thecarrier(s) must be “acceptable” in the sense of being compatible withthe other ingredients of the formulation and not deleterious to therecipient thereof.

Accordingly, the present invention further provides for a pharmaceuticalformulation comprising a compound of formula (1) or a pharmaceuticallyacceptable salt or solvate thereof together with one or morepharmaceutically acceptable carriers therefore and, optionally, othertherapeutic and/or prophylactic ingredients.

The formulations include those suitable for oral, parenteral (includingsubcutaneous e.g. by injection or by depot tablet, intradermal,intrathecal, intramuscular e.g. by depot and intravenous), rectal andtopical (including dermal, buccal and sublingual) administrationalthough the most suitable route may depend upon for example thecondition and disorder of the recipient. The formulations mayconveniently be presented in unit dosage form and may be prepared by anyof the methods well known in the art of pharmacy. All methods includethe step of bringing into association the compounds (“activeingredient”) with the carrier which constitutes one or more accessoryingredients. In general the formulations are prepared by uniformly andintimately bringing into association the active ingredient with liquidcarriers or finely divided solid carriers or both and then, ifnecessary, shaping the product into the desired formulation.

Formulations suitable for oral administration may be presented asdiscrete units such as capsules, cachets or tablets (e.g. chewabletablets in particular for paediatric administration) each containing apredetermined amount of the active ingredient; as a powder or granules;as a solution or a suspension in an aqueous liquid or a non-aqueousliquid; or as an oil-in-water liquid emulsion or a water-in-oil liquidemulsion. The active ingredient may also be presented as a bolus,electuary or paste.

A tablet may be made by compression or moulding, optionally with one ormore accessory ingredients. Compressed tablets may be prepared bycompressing in a suitable machine the active ingredient in afree-flowing form such as a powder or granules, optionally mixed with aother conventional excipients such as binding agents, (for example,syrup, acacia, gelatin, sorbitol, tragacanth, mucilage of starch orpolyvinylpyrrolidone), fillers (for example, lactose, sugar,microcrystalline cellulose, maize-starch, calcium phosphate orsorbitol), lubricants (for example, magnesium stearate, stearic acid,talc, polyethylene glycol or silica), disintegrants (for example, potatostarch or sodium starch glycollate) or wetting agents, such as sodiumlauryl sulfate. Moulded tablets may be made by moulding in a suitablemachine a mixture of the powdered compound moistened with an inertliquid diluent. The tablets may optionally be coated or scored and maybe formulated so as to provide slow or controlled release of the activeingredient therein. The tablets may be coated according to methods wellknown in the art.

Alternatively, the compounds of the present invention may beincorporated into oral liquid preparations such as aqueous or oilysuspensions, solutions, emulsions, syrups or elixirs, for example.Moreover, formulations containing these compounds may be presented as adry product for constitution with water or other suitable vehicle beforeuse. Such liquid preparations may contain conventional additives such assuspending agents such as sorbitol syrup, methyl cellulose,glucose/sugar syrup, gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminum stearate gel or hydrogenated edible fats;emulsifying agents such as lecithin, sorbitan mono-oleate or acacia;non-aqueous vehicles (which may include edible oils) such as almond oil,fractionated coconut oil, oily esters, propylene glycol or ethylalcohol; and preservatives such as methyl or propyl p-hydroxybenzoatesor sorbic acid. Such preparations may also be formulated assuppositories, e.g., containing conventional suppository bases such ascocoa butter or other glycerides.

Formulations for parenteral administration include aqueous andnon-aqueous sterile injection solutions which may contain anti-oxidants,buffers, bacteriostats and solutes which render the formulation isotonicwith the blood of the intended recipient; and aqueous and non-aqueoussterile suspensions which may include suspending agents and thickeningagents.

The formulations may be presented in unit-dose or multi-dose containers,for example sealed ampoules and vials, and may be stored in afreeze-dried (lyophilised) condition requiring only the addition of asterile liquid carrier, for example, water-for-injection, immediatelyprior to use. Extemporaneous injection solutions and suspensions may beprepared from sterile powders, granules and tablets of the kindpreviously described.

Formulations for rectal administration may be presented as a suppositorywith the usual carriers such as cocoa butter, hard fat or polyethyleneglycol.

Formulations for topical administration in the mouth, for examplebuccally or sublingually, include lozenges comprising the activeingredient in a flavoured basis such as sucrose and acacia ortragacanth, and pastilles comprising the active ingredient in a basissuch as gelatin and glycerin or sucrose and acacia.

The compounds may also be formulated as depot preparations. Such longacting formulations may be administered by implantation (for examplesubcutaneously or intramuscularly) or by intramuscular injection. Thus,for example, the compounds may be formulated with suitable polymeric orhydrophobic materials (for example as an emulsion in an acceptable oil)or ion exchange resins, or as sparingly soluble derivatives, forexample, as a sparingly soluble salt.

In addition to the ingredients particularly mentioned above, theformulations may include other agents conventional in the art havingregard to the type of formulation in question, for example thosesuitable for oral administration may include flavouring agents.

It will be appreciated by those skilled in the art that reference hereinto treatment extends to prophylaxis as well as the treatment ofestablished diseases or symptoms. Moreover, it will be appreciated thatthe amount of a compound of the invention required for use in treatmentwill vary with the nature of the condition being treated and the age andthe condition of the patient and will be ultimately at the discretion ofthe attendant physician or veterinarian. In general, however, dosesemployed for adult human treatment will typically be in the range of0.02-5000 mg per day, preferably 1-1500 mg per day. The desired dose mayconveniently be presented in a single dose or as divided dosesadministered at appropriate intervals, for example as two, three, fouror more sub-doses per day. The formulations according to the inventionmay contain between 0.1-99% of the active ingredient, conveniently from30-95% for tablets and capsules and 3-50% for liquid preparations.

The compound of formula (1) for use in the instant invention may be usedin combination with other therapeutic agents for example, statins and/orother lipid lowering drugs for example MTP inhibitors and LDLRupregulators. The compounds of the invention may also be used incombination with antidiabetic agents, e.g. metformin, sulfonylureasand/or PPAR gamma, PPAR alpha or PPAR alpha/gamma agonists (for examplethiazolidinediones such as e.g. Pioglitazone and Rosiglitazone). Thecompounds may also be used in combination with antihypertensive agentssuch as angistensin antagonists e.g. telmisartan, calcium channelantagonists e.g. lacidipine and ACE inhibitors e.g. enalapril. Theinvention thus provides in a further aspect the use of a combinationcomprising a compound of formula (1) with a further therapeutic agent inthe treatment of a hPPAR mediated disease.

When the compounds of formula (1) are used in combination with othertherapeutic agents, the compounds may be administered eithersequentially or simultaneously by any convenient route.

The combinations referred to above may conveniently be presented for usein the form of a pharmaceutical formulation and thus pharmaceuticalformulations comprising a combination as defined above optimallytogether with a pharmaceutically acceptable carrier or excipientcomprise a further aspect of the invention. The individual components ofsuch combinations may be administered either sequentially orsimultaneously in separate or combined pharmaceutical formulations.

When combined in the same formulation it will be appreciated that thetwo compounds must be stable and compatible with each other and theother components of the formulation and may be formulated foradministration. When formulated separately they may be provided in anyconvenient formulation, conveniently in such a manner as are known forsuch compounds in the art.

When a compound of formula (1) is used in combination with a secondtherapeutic agent active against the same hPPAR mediated disease, thedose of each compound may differ from that when the compound is usedalone. Appropriate doses will be readily appreciated by those skilled inthe art.

There is further provided processes for the preparation of compounds offormula (1). Unless otherwise indicated all definitions are as above.

Compounds of this invention may be conveniently prepared as illustratedbelow in schemes 4 through 7 utilizing moieties such as A through M anda variety of commercial or otherwise known reagents. Moieties A throughM are commercially available, known compounds or otherwise prepared asillustrated below in schemes 1, 2 and 3. In the following structures allvariables such as R¹, R², R⁴, R⁵, R⁶, and n are as defined above forformula (1) unless otherwise indicated. In the structures “A” representsC(R⁷)(R⁸) in formula (1) and R′, R⁹, R¹⁰, R¹¹, R¹², R¹³, R¹⁴, R¹⁷, R¹⁸,R¹⁹, and R²⁰ represent substituents for phenyl or heteroaryl groups asappropriate.

Scheme 1 below illustrates the general preparation of moieties A and B.In such a preparation, alkylation of 3- or 4-bromophenol with analpha-bromoalkanoic ester in the presence of a suitable base such asK₂CO₃, Cs₂CO₃ or NaH, followed by Palladium-catalyzed reaction withN-vinyl or allyl-phthalimide affords the olefin intermediates of generalformula N. Catalytic hydrogenation of the olefinic compounds N, followedby hydrazinolysis of the phtalimide group provides the primary aminemoieties A. These amine moieties A can be condensed with aldehydes underreductive amination conditions, or alkylated with alkyl halides toprovide the secondary amine moieties B.

Scheme 2 below illustrates the general preparation of moieties C and D.In such a preparation, condensation of 4-methoxy-benzaldehyde reagentswith nitromethane in the presence of NaOH, provides the correspondingnitroolefin derivatives which are subsequently reacted with a reducingagent such as borane to provide the primary amine moieties C. Aminemoieties C can be condensed with aldehydes under reductive aminationconditions, or alkylated with alkyl halides to provide the secondaryamine moieties D.

Scheme 3 bellow illustrates an alternative synthetic route for thepreparation of moieties B and D. In such a preparation, condensation of4-hydroxy- or methoxy phenethylamine reagents with aldehydes underreductive amination conditions provides the secondary amine moieties D.Moieties D in which R′ is methyl can be O-demethylated with a reagentsuch as boron tribromide to provide the corresponding unmasked phenolderivatives. These phenol derivatives can be O-alkylated withalpha-bromoalkanoic esters in the presence of a suitable base such asNaH to provide moieties B.

Scheme 4 below illustrates a general preparation of compounds of generalformula (1) in which R³ is one of the following: benzoxazole,benzothiazole, oxazole, pyrimidine, pyridazine, pyrazine or pyridine.Such a route involves the condensation of a moiety such as A, B, C or D,with a 2-chloro (or bromo)-heterocyclic reagent, such as moieties Hthrough M, at elevated temperatures to provide compounds of generalformula O or P. Wherein a primary amine moiety such as A or C is used,the ensuing product O can be further derivatized by alkylation with analkyl halide using a suitable base, such as NaH, to provide alsointermediates of general formula P.

Intermediates of general formula P which are derived from moieties suchas A or B have their carboxylic acid functionalities protected as thecorresponding methyl, ethyl or tert-butyl esters. Hydrolysis of theseesters (with LiOH or NaOH for the methyl and ethyl esters and with TFAfor the tert-butyl esters) provides the corresponding carboxylic acidsof general formula (1).

Intermediates of general formula P which are derived from moieties suchas C or D have their phenol moieties protected as the correspondingmethyl ethers. These can be demethylated using a reagent such as borontribromide and the corresponding unmasked phenol derivatives can beconverted to carboxylic acids or tetrazole compounds of formula (1) byone of the three synthetic protocols illustrated in schemes 8 through10.

In the first protocol, as illustrated in scheme 8, the unmasked phenolcan be alkylated directly with 2-trichloromethyl-2-propanol using NaOHin acetone to provide carboxylic acids of formula (1) whereinR¹=R²=methyl.

In the second protocol, as illustrated in scheme 9, the unmasked phenolcan be alkylated with an alpha-chloro (or bromo) alkanoic ester toprovide the corresponding alpha-phenoxy esters, which are subsequentlyhydrolyzed to carboxylic acids of formula (1).

In the third protocol, as illustrated in scheme 10, the unmasked phenolis alkylated with chloroacetonitrile using a suitable base such asCs₂CO₃ to provide the corresponding alpha-phenoxy-acetonitrilederivatives. These nitrile intermediates can be reacted at elevatedtemperatures with trimethylsilyl azide under dibutyltin oxide catalysisto provide tetrazole compounds of formula (1) wherein R¹=R²=hydrogen.

Scheme 5 below illustrates a general preparation of compounds of formula(1) in which R³ is a pyridine ring. Such a route involves the couplingof a carboxylic acid moiety G to a 2-amino-pyridine moiety F, mediatedby a suitable coupling agent such as EDCI. The resulting amideintermediate can be reacted with a reducing agent such LAH to providethe corresponding 2-alkylamino-pyridine of general formula Q. Amines Qcan be subsequently derivatized by alkylation with an alkyl halide toprovide compounds of general formula R. Compounds of general formula Rhave their phenol moieties protected as the corresponding methyl etherderivatives. Deprotection of these methyl ethers with a reagent such asboron tribromide provides the corresponding phenol derivatives, whichcan be converted to carboxylic acids or tetrazoles of general formula(1) utilizing one of the three protocols mentioned above and illustratedin schemes 8, 9, and 10.

Scheme 6 below illustrates the preparation of compounds of formula (1)in which R³ is 1,2,4-oxadiazole. Such a route involves the coupling of asecondary amine moiety B, with cyanogen bromide to provide thecorresponding cyanoamine derivative which is subsequently reacted withhydroxylamine to afford N-hydroxy-guanidine compounds of general formulaS. These intermediates of formula S can be reacted with an acid chloridein the presence of a suitable base, or with a carboxylic acid mediatedby a suitable coupling agent to provide, upon heating,3-amino-1,2,4-oxadiazole derivatives of general formula T. Intermediatesof formula T can be converted to carboxylic acids of general formula (1)by hydrolysis or their ester moieties.

Scheme 7 below illustrates the preparation of compounds of formula (1)in which R³ is 1,3-thiazole. Such a route involves the condensation of asecondary amine moiety B with ammonium thiocyanate at elevatedtemperatures to provide thiourea derivatives of general formula U. Theseintermediates are subsequently condensed with phenacyl bromide reagentsto afford 2-amino-1,3-thiazole compounds of formula V. The esterfunctionality present in compounds of formula V can be hydrolyzed withLiOH or NaOH to provide the carboxylic acid compounds of formula (1).

Scheme 8 below illustrates the one-step preparation of carboxylic acidsof general formula (1) by alkylation of intermediate compounds ofgeneral formula X with 2-trichloromethyl-2-propanol and NaOH.

Scheme 9 below illustrates the preparation of carboxylic acids ofgeneral formula (1) by a two-step process in which a phenol compound ofgeneral formula X is first alkylated with an alpha-bromo alkanoic esterreagent and subsequently the ester moiety is hydrolyzed with lithium orsodium hydroxide (in the case of methyl or ethyl ester derivatives) orwith TFA (in the case of tert-butyl ester derivatives).

Scheme 10 below illustrates the preparation of tetrazole compounds offormula (1) by a two-step process in which an intermediate phenol moietyX is first alkylated with chloroacetonitrile and subsequently thenitrile moiety converted to a tetrazole moiety by reaction withtrimethylsilylazide at elevated temperatures under dibutyltin oxidecatalysis.

In addition to the general preparation routes illustrated above, it canbe appreciated by those skilled in the art that some intermediatesgenerated during the synthesis of compounds of formula (1) can befurther derivatized when an appropriate functional group (such as, forexample, bromo, nitro, hydroxyl or carbonyl) is present that would makethe molecule amenable to further chemical modification using standardsynthetic procedures and reagents.

For example, the intermediate bromo compound X1 below, which wasgenerated during a process such as that exemplified in scheme 4, wasreacted with phenylboronic acid under standard Suzuki conditions toprovide a novel phenyl derivative, which upon hydrolysis provided anovel compound of formula (1).

In another example, an aldehyde intermediate, such as compound X2 below,similarly generated during a process such as that illustrated in scheme4, was reacted with isopropyltriphenylphosphoniumbromide/n-butyl lithiumunder standard Wittig conditions to provide a novel alkene compoundwhich after catalytic hydrogenation and ester hydrolysis provided anovel compound of formula (1).

The invention is further illustrated by the following examples, whichshould not be construed as constituting a limitation thereto.

EXAMPLES

The structures of the compounds were confirmed by either nuclearmagnetic resonance (NMR) or mass spectrometry (MS). Proton NMR (¹H NMR)spectra were recorded on a Brucker 300 or 400 MHz spectrometer atambient temperature. NMR shifts (δ) are given in parts per million(ppm). Coupling constants (J) are given in Hertzs.

Chromatography refers to standard silica gel flash column chromatographyor to radial chromatography (using a Chromatotron apparatus).

Compounds used as starting materials are either commercially availableor known compounds.

Abbreviations:

TLC: thin layer chromatography

rt: room temperature

h or hr: hour

eq: equivalent

EDCI: 1-ethyl-3-(3-dimethyl-aminopropyl) carbodiimide

LAH: lithium aluminum hydride

BH₃: borane

NaHMDS: sodium bis(trimethylsilyl)amide

TFA: trifluoroacetic acid

Na₂CO₃: sodium carbonate

Cs₂CO₃: cesium carbonate

NaH: sodium hydride

MeOH: methanol

EtOH: ethanol

DMF: dimethylformamide

THF: tetrahydrofuran

EtOAc: ethyl acetate

CDCl₃: deuterated chloroform

CD₃OD: deuterated methanol

Acetone-D₆: deuterated acetone

NaOMe: sodium methoxide

DIEA: diisopropylethylamine

NaOH: sodium hydroxide

LiOH: lithium hydroxide

HCl: hydrochloric acid

MeCN: acetonitrile

MgSO₄: magnesium sulfate

What follows are common procedures that were routinely used in thecourse of preparing the compounds of this invention. In the subsequentexperimental section we might refer to these common procedures and noteonly specific changes or conditions that deviated from these commonprocedures.

Procedure A: Reductive Amination.

A solution of a primary amine in MeOH (0.1-0.5 M) was treated undernitrogen with 1 eq of the aldehyde and 5 eq of trimethylorthoformate.After stirring at rt for 12 hours, 2.5 eq of sodium borohydride wereadded in small portions (exothermic). Stirred for one hour andconcentrated in a rotary evaporator. The residue was partitioned betweenequal volumes of ethyl acetate and water. The organic phase was washedwith saturated brine, dried over sodium sulfate, filtered andconcentrated to provide the secondary amine derivative. The crude aminewas carried on to the next step without further purification or,alternatively, it was purified by flash chromatography on silica gelusing ethyl acetate-hexane mixtures (5-50% gradient) ormethanol-dichloromethane mixtures (1-10% gradient).

Procedure B: Alkylation of Primary Amines with an Alkyl Chloride orBromide Reagent.

A solution of a primary amine in dichloromethane (0.1-0.5M) was treatedwith 1 eq of DIEA and 1 eq of the chloride or bromide reagent. Afterstirring at rt for 12 hours the mixture was concentrated and partitionedbetween equal volumes of ethyl acetate and saturated Na₂CO₃. The organicphase was washed with saturated Na₂CO₃ and brine, dried over sodiumsulfate and concentrated to dryness. Purification by chromatography onsilica gel using ethyl acetate-hexane mixtures (10-50% gradient)afforded the secondary amines derivatives.

Procedure C: Alkylation of Phenolic Compounds with Bromide or ChlorideReagents.

A solution of a phenolic compound in a solvent such as MeCN, THF or DMF(0.1-0.5 M) was treated under nitrogen with 1.1-2.2 eq of a base such asCs₂CO₃, K₂CO₃. After stirring at rt for 10 minutes, 1.1-2 eq of thebromide or chloride reagent was added and the mixture heated at 75C for2-14 hours. Upon cooling, the mixture was concentrated and the residuepartitioned between equal volumes of ethyl acetate and water. Theorganic phase was washed with saturated brine, dried over sodiumsulfate, filtered and concentrated to dryness. Purification bychromatography on silica gel using ethyl acetate-hexane mixtures (5-50%gradient) provided the alkylated phenol derivative.

Procedure D: Alkylation of Phenolic Compounds with2-trichloromethyl-2-propanol.

A solution of a phenolic compound in acetone (0.25 M) was treated with 8eq of NaOH (triturated; slowly, in small portions) and 3 eq of water.After stirring for 10-40 minutes, a solution of 1.5 eq of2-trichloromethyl-2-propanol in acetone (1M) was added and the mixturestirred at rt for 12 hours. The reaction mixture was concentrated in arotary evaporator and the residue partitioned between equal volumes ofethyl acetate and water. An aqueous solution of HCl was added to adjustthe pH to ˜4. The phases were separated and the aqueous phase wasextracted with an equal volume of ethyl acetate. The combined organicphases were washed with saturated brine, dried over sodium sulfate andconcentrated to provide the crude 2-methyl-2-phenoxy-propanoic acidderivatives. When needed, as judged by TLC, the crude acid was purifiedby chromatography on silica gel using methanol-dichloromethane mixtures(1-10% gradient) or methanol-ethyl acetate mixtures (0.5-15% gradient).Alternatively the acid could be crystallized directly or used withoutany further purification.

Procedure E: Condensation of Amines with 2-chloro(or Bromo)-pyrimidineReagents.

A pressure tube containing a primary or secondary amine, either neat orin a solvent such as toluene, n-butanol or dioxane (0.5-1M) was treatedunder nitrogen with 1.1-3 eq of the 2-chloro(or bromo)-pyrimidinereagent and 1.1-3 eq of a base such as DIEA or K₂CO₃. The mixture wasthen heated to 120-230C for 14-72 hours. Upon cooling, the mixture waspartitioned between equal volumes of ethyl acetate and water. Theaqueous phase was washed with an equal volume of ethyl acetate and thecombined organic phases were washed with saturated brine, dried oversodium sulfate, filtered and concentrated to dryness. Purification bychromatography on silica gel using ethyl acetate-hexane mixtures (2-30%gradient) provided the 2-amino-pyrimidine derivatives.

Procedure F: Demethylation of Methyl Aryl Ethers with Boron Tribromide.

A solution of a methyl aryl ether in dichloromethane (0.1-0.5M) wastreated under nitrogen, in an ice bath, with 2-4 eq of boron tribromide(commercial 1M solution in dichloromethane). The mixture was stirred for1-4 hours and then quenched by careful addition of ice in small portions(exothermic). The mixture was diluted with one volume of water, the pHadjusted to ˜6 with saturated K₂CO₃ solution and the phases separated.The aqueous phase was washed with ethyl acetate and the combined organicphases were washed with saturated brine, dried over sodium sulfate andconcentrated to provide the crude phenol.

An alternative workup procedure involved quenching the reaction bycareful addition of a few mls of MeOH, concentrating the mixture andazeotroping from MeOH. The residue was then redissolved in MeOH, treatedwith 1 eq of NaOMe and concentrated. This was followed by a standardaqueous workup.

The crude phenol was used directly or purified by chromatography onsilica gel using ethyl acetate-hexane mixtures (10-50% gradient).

Procedure G: Demethylation of Methyl Aryl Ethers with PyridiniumHydrochloride.

A mixture of a methyl aryl ether and pyridinium hydrochloride (5-20weight equivalent) was heated at 220C for 20-60 minutes. Upon coolingthe mixture was partitioned between equal volumes of ethyl acetate andwater. The organic phase was washed with saturated brine, dried oversodium sulfate and concentrated to dryness. Purification bychromatography on silica gel using ethyl acetate-hexane mixtures (10-50%gradient) provided the phenol derivative.

Procedure H: Base-Mediated Ester Hydrolysis.

A solution of a methyl or ethyl ester in 1:1 THF:MeOH (0.1-0.5M) wastreated with 3-10 eq of 1N NaOH or LiOH and heated to 65C for 2-6 hours.The reaction mixture was concentrated in a rotary evaporator andpartitioned between equal volumes of ethyl acetate and water. The pH wasadjusted to ˜6 with 1N HCl and the phases separated. The aqueous phasewas washed with ethyl acetate and the combined organic phases werewashed with saturated brine, dried over sodium sulfate and concentratedto dryness. When needed, as judged most commonly by TLC, the materialwas purified by chromatography on silica gel usingmethanol-dichloromethane mixtures (1-10% gradient) or methanol-ethylacetate mixtures (1-15% gradient) to provide the desired carboxylicacid. Alternatively the crude acid was crystallized directly or usedwithout any further purification.

Procedure I: Acid-Mediated Ester Hydrolysis.

A solution of a tert-butyl ester in dichloromethane (0.1-0.5M) wastreated with triethylsilane (0.2 volumes) and trifluoroacetic acid (0.5volumes). After stirring for 2-6 hours the mixture was concentrated todryness and then azeotroped from chloroform four times. Purification bychromatography on silica gel using methanol-dichloromethane mixtures(1-10% gradient) provided the carboxylic acid derivative. Alternativelythe acid was crystallized directly or used without any furtherpurification.

PREPARATION OF INTERMEDIATES AND EXAMPLES

tert-Butyl 2-[3-(2-aminoethyl)phenoxy]-2-methylpropanoate

Step 1.

To a solution of 3-bromophenol (55.4 g; 0.32 mol) in acetone (1000 ml)at 0° C. was added chloretone (108.25 g; 0.61 mol) followed byportionwise addition of sodium hydroxide (3 times 33.3 g; total 100 g;2.39 mole). After the first two portions, the mixture was allowed towarm to 23° C. for 1 h and then cooled to 0C; after the third additionthe mixture was stirred at 23° C. for 18 h. The organic solvent wasremoved by evaporation and the residue was dissolved in water (1500 ml)and acidified to pH 2 with concentrated HCl to afford a red oil. Themixture was extracted with methylene chloride (3×500 ml) and thecombined organic layers were dried (Na₂SO₄) and evaporated to afford2-(3-bromophenoxy)-2-methylpropionic acid as a dark oil (82.66 g;99.6%).

¹H NMR (CDCl₃)δ 7.14 (m, 3H), 6.86 (d, 1H, J=6), 1.63 (s, 6H).

Step 2.

A solution of the above intermediate (82.66 g; 0.32 mole) andconcentrated sulfuric acid (5 ml) in methylene chloride (500 ml) wascooled to −78° C. and isobutylene was distilled into the reactionmixture (150 ml). The mixture was allowed to warm to rt and stirred for18 hr. The acid was then carefully neutralized by the addition ofsaturated sodium bicarbonate solution. The organic layer was separated,dried (Na₂SO₄), and concentrated. The residue was purified bychromatography to afford t-butyl 2-(3-bromophenoxy)-2-methylpropionateas an oil (68 g; 70%).

¹H NMR (CDCl₃) δ 8 7.08 (d, 2H, J=5), 7.01 (s, 1H), 6.78 (m, 1H), 1.60(s, 6H), 1.44 (s, 9H).

Step 3.

A mixture of the above intermediate (1 eq), N-vinylphthalimide (1.05eq), palladium acetate (0.05 eq), tri-o-tolylphosphine (0.10 eq) andtriethylamine (2 eq) in a sealed tube was heated at 110° C. for 15 h.The solvent was evaporated and the residue partitioned between 2N HCland ethyl acetate and filtered through celite. The aqueous phase waswashed with ethyl acetate. The combined organic phases were washed withbrine, dried (MgSO₄) and concentrated. The residue was purified bychromatography using EtOAc-Hexane-CH₂Cl₂ as eluant to afford t-butyl2-(3-(2-phthalimidoethenyl)phenoxy)-2-methylpropionate as a yellowsolid.

¹H NMR (CDCl₃) δ 7.88 (m, 2H), 7.75 (m, 2H), 7.58 (d, 2H, J=15), 7.30(d, 1H, J=15), 7.20 (t, 1H, J=7), 7.08 (d, 1H, J=7), 6.98 (s, 1H), 6.75(dd, 1H, J=8 and 2), 1.6 (s, 6H), 1.43 (s, 9H).

Step 4.

A solution of the above intermediate in chloroform (0.5 M) was treatedwith 10% Pd/C (0.1 equivalent weight) and hydrogenated in a Parrapparatus under 40 psi of H₂ for 6 hr. The mixture was filtered throughcelite and the filtrate was concentrated to afford t-butyl2-(3-(2-phthalimidoethyl)phenoxy)-2-methylpropionate as an oil.

¹H NMR (CDCl₃) δ 7.82 (m, 2H), 7.70 (m, 2H), 7.14 (t, 1H, J=8), 6.87 (d.1H, J=8), 6.76 (s, 1H), 6.70 (d, 1H, J=8), 3.89 (t, 2H, J=8), 2.92 (t,2H, J=8), 1.51 (s, 6H), 1.44 (s, 9H).

Step 5.

A solution of the above intermediate (1 eq) in ethanol (4M) was treatedwith hydrazine hydrate (3 eq) and heated at reflux for 5 hours. Uponcooling, the reaction mixture stood at rt for 15 hr. The resultantsolids were filtered off and the filtrate was concentrated. The residuewas partitioned between 1N NaOH and ethyl ether. The organic phase waswashed with 1N NaOH and brine, dried (MgSO₄) and concentrated to affordthe title compound as an oil in good yield.

¹H NMR (CDCl₃) δ 7.15 (t, 1H, J=8), 6.80 (d, 1H, J=8), 6.72 (s, 1H),6.69 (d, 1H, J=8), 2.94 (t, 2H, J=7), 2.68 (t, 2H, J=7), 1.56 (s, 6H),1.44 (s, 9H), 1.15 (brs, 2H).

tert-Butyl 2-[4-(2-aminoethyl)phenoxy]-2-methylpropanoate

Similarly prepared from 4-bromo-phenol and vinyl phtalimide.

¹H NMR (CDCl₃) δ 7.05 (d, 2H, J=8), 6.80 (d, 2H, J=8), 2.92 (t, 2H,J=7), 2.67 (t, 2H, J=7), 1.54 (s, 6H), 1.44 (s, 9H), 1.32 (brs, 2H).

tert-Butyl 2-[3-(3-aminopropyl)phenoxy]-2-methylpropanoate

Similarly prepared from 3-bromo-phenol and allyl phtalimide.

¹H NMR (CDCl₃) δ 7.12 (t, 1H, J=8), 6.79 (d, 1H, J=8), 6.70 (s, 1H),6.66 (d, 1H, J=8), 2.70 (t, 2H. J=7), 2.59 (t, 2H, J=7), 1.74 (m, 2H),1.56 (s, 6H), 1.44 (s, 9H).

tert-Butyl 2-[4-(3-aminopropyl)phenoxy]-2-methylpropanoate

Similarly prepared from 4-bromo-phenol and allyl phtalimide.

¹H NMR (CDCl₃) δ 7.03 (d, 2H, J=8), 6.78 (d, 2H, J=8), 2.70 (t, 2H,J=6), 2.57 (t, 2H, J=6), 1.72 (m, 2H), 1.54 (s, 6H), 1.44 (s, 9H), 1.18(brs, 2H).

4-(5-Isopropyl-1,2,4-oxadiazol-3-yl)benzaldehyde

Step 1.

A suspension of hydroxylamine hydrochloride (31.62 g; 45.5 mmol) in MeOH(350 ml) was treated with sodium methoxide (24.58 g; 45.5 mmol) slowly,in small portions. After stirring for 20 minutes, a solution of4-(dimethoxymethyl)benzonitrile (67 g; 37.9 mmol) in MeOH (100 ml) wasadded and the mixture heated to reflux. After 12 hr, it was concentratedand partitioned between ethyl acetate and water. The organic phase waswashed with water and brine, dried over sodium sulfate, filtered andconcentrated to afford4-(dimethoxymethyl)-N′-hydroxybenzenecarboximidamide (74.2 g) which wasused in the next step without further purification. MS: m/z 211 (M+1).

Step 2.

A solution of the previous intermediate (7 g; 33.3 mmol) in pyridine (30ml) was treated under nitrogen with isobutyryl chloride (3.7 ml; 34.99mmol) and heated to reflux for 2 hours. Upon cooling, the mixture waspartitioned between ethyl acetate and 1N HCl. The organic phase waswashed with 1N HCl, water (2×), 1N NaOH and brine, dried over sodiumsulfate and concentrated. Purification by flash chromatography using anethyl acetate-hexane gradient (10-50%) afforded the title compound as awhite solid (4.23 g; 59% yield).

¹H NMR (CDCl₃) δ 10.12 (s, 1H), 8.29 (d, 2H, J=8.2), 8.02 (d, 2H,J=8.2), 3.35 (m, 1H), 1.50 (d, 6H, J=7.0).

4-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)benzaldehyde

Similarly prepared using cyclopropane carbonyl chloride.

¹H NMR (CDCl₃) δ 10.1 (s, 1H), 8.27 (d, 2H, J=8.2), 7.98 (d, 2H, J=8.2),2.28 (m, 1H), 1.30 (m, 4H).

tert-Butyl2-[3-(3-{[4-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)benzyl]amino}propyl)phenoxy]-2-methylpropanoate

Reductive amination of tert-butyl2-[3-(3-aminopropyl)phenoxy]-2-methylpropanoate with4-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)benzaldehyde as per generalprocedure A afforded after column chromatography the title compound in81% yield.

¹H NMR (CDCl₃) δ 7.98 (d, 2H, J=8.2), 7.42 (d, 2H, J=8.2), 7.11 (t, 1H,J=7.8), 6.77 (d, 1H, J=7.8), 6.69 (bs, 1H), 6.65 (dd, 1H, J=7.8; 2.2),3.83 (s, 2H), 2.66 (t, 2H, J=7.2), 2.60 (t, 2H, J=7.6), 2.24 (m, 1H),1.84 (m, 2H), 1.55 (s, 6H), 1.42 (s, 9H), 1.30 (m, 4H).

tert-Butyl2-[4-(2-{[4-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)benzyl]amino}ethyl)phenoxy]-2-methylpropanoate

Similarly prepared by reductive amination of tert-butyl2-[4-(2-aminoethyl)phenoxy]-2-methylpropanoate with4-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)benzaldehyde (85% yield). ¹HNMR(CDCl₃) δ 8.00 (d, 2H, J=8.2), 7.41 (d, 2H, J=8.2), 7.08 (d, 2H, J=8.5),6.82 (d, 2H, J=8.5), 3.88 (s, 2H), 2.90 (t, 2H, J=6.6), 2.80 (t, 2H,J=6.6), 2.28 (m, 1H), 1.57 (s, 6H), 1.47 (s, 9H), 1.30 (m, 4H). MS: m/z478 (M+1).

Ethyl2-[4-(2-{[4-(5cyclopropyl-1,2,4-oxadiazol-3-yl)benzyl]amino}ethyl)phenoxy]-2-methylpropanoate

Similarly prepared by reductive amination of ethyl2-[4-(2-aminoethyl)phenoxy]-2-methylpropanoate with4-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)benzaldehyde (61% yield). ¹H NMR(CDCl₃) δ 7.85 (d, 2H, J=8.1), 7.23 (d, 2H, J=8.1), 6.93 (d, 2H, J=8.4),6.66 (d, 2H, J=8.4), 4.09 (q, 2H, J=7.0), 3.68 (s, 2H), 2.71 (t, 2H,J=6.6), 2.61 (t, 2H, J=6.6), 2.08 (m, 1H), 1.45 (s, 6H), 1.12 (m, 7H).

Methyl2-[4-(2-{[4-(5-isopropyl-1,2,4-oxadiazol-3-yl)benzyl]amino}ethyl)phenoxy]-2-methylpropanoate

A solution of methyl 2-[⁴-(²-aminoethyl)phenoxy]-2-methylpropanoate (1g; 4.22 mmol) in dichloromethane (30 ml) was treated under nitrogen with4-(5-isopropyl-1,2,4-oxadiazol-3-yl)benzaldehyde (0.96 g; 4.43 mmol),sodium triacetoxyborohydride (0.94 g; 4.43 mmol) and acetic acid (0.24ml; 4.23 mmol). After stirring at rt overnight, the mixture wasconcentrated and partitioned between ethyl acetate and 1N NaOH. Theorganic phase was washed with brine, dried over sodium sulfate, filteredand concentrated. Purification by flash chromatography using an ethylacetate-hexane gradient (20-70%) followed by a methanol-dichloromethanegradient (1-10%) afforded the title compound (1.5 g; 81% yield).

¹H NMR (CDCl₃) δ 7.96 (d, 2H, J=8.1), 7.32 (d, 2H, J=8.1), 7.0 (d, 2H,J=8.5), 6.70 (d, 2H, J=8.5), 3.78 (s, 2H), 3.70 (s, 3H), 3.21 (m, 1H),2.80 (t, 2H, J=6.9), 2.70 (t, 2H, J=6.9), 1.51 (s, 6H), 1.39 (d, 6H,J=6.9).

tert-Butyl2-methyl-2-[3-(3-{[4-(trifluoromethyl)benzyl]amino}propyl)phenoxy]propanoate

Reductive amination of tert-butyl2-[3-(3-aminopropyl)phenoxy]-2-methylpropanoate with 4-trifluoromethylbenzaldehyde as per general procedure A afforded after columnchromatography the title compound in 49% yield.

¹H NMR (CDCl₃) δ 7.58 (d, 2H, J=8.1), 7.44 (d, 2H, J=8.1), 7.13 (t, 1H,J=7.8), 6.79 (d, 1H, J=7.8), 6.72 (bs, 1H), 6.71 (dd, 1H, J=7.8 and2.4), 3.83 (s, 2H), 2.64 (m, 4H), 1.83 (m, 2H), 1.57 (s, 6H), 1.45 (s,9H). MS: m/z 452 (M+1).

tert-Butyl2-methyl-2-[4-(2-{[4-(trifluoromethyl)benzyl]amino}ethyl)phenoxy]propanoate

Reductive amination of tert-butyl2-[4-(2-aminoethyl)phenoxy]-2-methylpropanoate with 4-trifluoromethylbenzaldehyde as per general procedure A afforded after columnchromatography the title compound in 93% yield.

¹H NMR (CDCl₃) δ 7.53 (d, 2H, J=8.1), 7.36 (d, 2H, J=8.1), 7.04 (d, 2H,J=8.6), 6.78 (d, 2H, J=8.6), 3.82 (s, 2H), 2.83 (t, 2H, J=6.7), 2.74 (t,2H, J=6.7), 1.58 (s, 6H), 1.42 (s, 9H).

4-(2-{[4-(Trifluoromethyl)benzyl]amino}ethyl)phenol

A suspension of tyramine (1 g; 7.29 mmol) in MeOH (8 ml) was treatedwith 4-trifluoromethyl benzaldehyde (1.27 g; 7.29 mmol) andtrimethylorthoformate (5 ml). The reaction mixture was stirred at rtovernight and then treated with sodium borohydride (0.69 g; 18.23 mmol)in small portions. After stirring for 30 minutes, it was concentratedand partitioned between ethyl acetate and water. The organic phase waswashed with brine, dried over sodium sulfate, filtered and concentrated.Crystallization from ethyl ether-hexane provided the title compound as awhite crystalline solid (1.67 g; 78% yield). ¹H NMR (CDCl₃) δ 7.54 (d,2H, J=8.0), 7.37 (d, 2H, J=8.0), 7.00 (d, 2H, J=8.4), 6.68 (d, 2H,J=8.4), 4.50 (bs, 2H), 3.86 (s, 2H), 2.88 (t, 2H, J=6.9), 2.77 (t, 2H,J=6.9).

Ethyl2-methyl-2-[4-(2-{[4-(trifluoromethyl)benzyl]amino}ethyl)phenoxy]propanoate

A solution of 4-(2-{[4-(trifluoromethyl)benzyl]amino}ethyl)phenol (1 g;3.39 mmol) in THF (10 ml) was treated under nitrogen with NaH (0.14 g ofa 60% dispersion in oil; 3.56 mmol). After stirring for 10 minutes,ethyl-2-bromo isobutyrate (0.69 g; 3.56 mmol) was added and the mixtureheated at 75C for 12 hr. Upon cooling, additional sodium hydride (0.040g; 1.01 mmol) and bromide (0.21 g; 1.06 mmol) were added. After heatingat 75C for 3 hr, the mixture was concentrated and partitioned betweenethyl acetate and 1N NaOH. The organic phase was washed with 1N NaOH andbrine, dried over sodium sulfate and concentrated. Purification by flashchromatography on silica gel using a methanol-dichloromethane gradient(1-10%) afforded the title compound (1.12 g; 80% yield).

¹H NMR (CDCl₃) δ 7.50 (d, 2H, J=8.0), 7.35 (d, 2H, J=8.0), 7.03 (d, 2H,J=8.4), 6.76 (d, 2H, J=8.4), 4.18 (q, 2H, J=7.1), 3.79 (s, 2H), 2.81 (t,2H, J=6.8), 2.72 (t, 2H, J=6.8), 1.55 (s, 6H), 1.20 (t, 3H, J=7.1).

Methyl2-[4-(2-{[2,4-bis(trifluoromethyl)benzyl]amino}ethyl)phenoxy]-2-methylpropanoate

A solution of methyl 2-[4-(2-aminoethyl)phenoxy]-2-methylpropanoate(Biochim. Biophys. Acta 1997, 1339 (2), 321-330) (2 g; 8.44 mmol) indichloromethane (20 ml) was treated with DIEA (1.47 ml; 8.44 mmol) and2,4-bis-trifluoromethyl-benzyl bromide (2.59 g; 8.44 mmol). Afterstirring at rt overnight, the reaction mixture was concentrated andpartitioned between ethyl acetate and saturated Na₂CO₃ solution. Theorganic phase was washed with Na₂CO₃ solution and brine, dried oversodium sulfate and concentrated. Purification by flash chromatography onsilica gel using an ethyl acetate-hexane mixture (10-50%) afforded thetitle compound (2.0 g; 51% yield).

¹H NMR (CDCl₃) δ 7.83 (s, 1H), 7.79 (d, 1H, J=8.3), 7.73 (d, 1H, J=8.3),7.04 (d, 2H, J=8.4), 6.74 (d, 2H, J=8.4), 3.99 (s, 2H), 3.74 (s, 3H),2.86 (t, 2H, J=6.8), 2.75 (t, 2H, J=6.8), 1.55 (s, 6H). MS: m/z 464(M+1).

Methyl2-methyl-2-[4-(2-{[4-(trifluoromethyl)benzyl]amino}ethyl)phenoxy]propanoate

Similarly, alkylation of methyl2-[4-(²-aminoethyl)phenoxy]-2-methylpropanoate with 4-trifluoromethylbenzyl bromide afforded the title compound in 52% yield.

¹H NMR (CDCl₃) δ 7.52 (d, 2H, J=8.0), 7.36 (d, 2H, J=8.0), 7.05 (d, 2H,J=8.4), 6.76 (d, 2H, J=8.4), 3.81 (s, 2H), 3.74 (s, 3H), 2.82 (t, 2H,J=6.8), 2.73 (t, 2H, J=6.8).

tert-Butyl2-[3-(3-{[2,4-bis(trifluoromethyl)benzyl]amino}propyl)phenoxy]-2-methylpropanoate

Similarly, alkylation of tert-butyl2-[3-(3-aminopropyl)phenoxy]-2-methylpropanoate with2,4-bis-trifluoromethyl-benzyl bromide afforded the title compound in38% yield. ¹H NMR (CDCl₃) δ 7.86 (m, 2H), 7.77 (d, 1H, J=8.3), 7.11 (t,1H, J=7.9), 6.77 (d, 1H, J=7.7), 6.69 (bs, 1H), 6.64 (dd, 1H, J=8.1;2.4), 3.99 (s, 2H), 2.66 (t, 2H, J=7.0), 2.60 (t, 2H, J=7.7), 1.83 (m,2H), 1.53 (s, 6H), 1.41 (s, 9H).

Ethyl2-methyl-2-[4-(2-{[4-(trifluoromethoxy)benzyl]amino}ethyl)phenoxy]propanoate

Step 1.

A solution of tyramine (8.56 g; 62.41 mmol) in MeOH (60 ml) was treatedwith 4-trifluoromethoxy benzaldehyde (11.3 g; 59.4 mmol) andtrimethylorthoformate (32 ml) under a nitrogen atmosphere. Afterstirring at rt overnight, the reaction mixture was cooled in an ice bathand treated with sodium borohydride (5.65 g; 148.6 mmol) in smallportions. The mixture was stirred for 1.5 hr and then concentrated. Theresidue was partitioned between ethyl acetate and water. The organicphase was washed with brine, dried over sodium sulfate, filtered andconcentrated to afford4-(2-{[4-(trifluoromethyl)benzyl]amino}ethyl)phenol, which was used inthe next step without further purification.

Step 2.

A solution of the previous intermediate (˜62.41 mmol) in MeCN (100 ml)was treated under nitrogen with Cs2CO3 (40.66 g; 124.8 mmol) andethyl-2-bromo-isobutyrate (24.34 g; 124.8 mmol). After heating at 80Cfor 5 hr, the reaction mixture was concentrated and the residue waspartitioned between ethyl acetate and water. The organic phase waswashed with brine, dried over sodium sulfate, filtered and concentrated.Purification by flash chromatography on silica gel using an ethylacetate-hexane gradient (20-80%), followed by a methanol-dichloromethanegradient (1-10%) afforded the title compound (19.4 g; 74% yield).

¹H NMR (CDCl₃) δ 7.26 (d, 2H, J=8.5), 7.11 (d, 2H, J=8.5), 7.03 (d, 2H,J=8.5), 6.75 (d, 2H, J=8.5), 4.20 (q, 2H, J=7.1), 3.75 (s, 2H), 2.82 (t,2H, J=6.6), 2.72 (t, 2H, J=6.6), 1.55 (s, 6H), 1.22 (t, 3H, J=7.1).

Ethyl2-methyl-2-(4-{2-[(pyridin-3-ylmethyl)amino]ethyl}phenoxy)propanoate

Similarly prepared from tyramine and 3-pyridine carboxaldehyde.

Ethyl2-methyl-2-(4-{2-[(pyridin-4-ylmethyl)amino]ethyl}phenoxy)propanoate

Similarly prepared from tyramine and 4-pyridine carboxaldehyde.

Ethyl2-[2-methoxy-4-(2-{[4-(trifluoromethyl)benzyl]amino}ethyl)phenoxy]-2-methylpropanoate

Similarly prepared from 4-(2-aminoethyl)-2-methoxyphenol and4-trifluoromethyl benzaldehyde.

Ethyl2-[2-bromo-4-(2-{[4-(trifluoromethyl)benzyl]aminoethyl)phenoxy]-2-methylpropanoate

Step 1.

Reductive amination of 3-bromo-4-methoxyphenethylamine (10 g; 4.35 mmol)with 4-trifluoromethyl benzaldehyde (7.57 g; 4.35 mmol) as per generalprocedure A provided after workupN-[2-(3-bromo-4-methoxyphenyl)ethyl]-N-[4-(trifluoromethyl)benzyl]amine(15.2 g; 90% yield), which was used in the next step without furtherpurification.

Step 2.

Demethylation of the previous intermediate with boron tribromide as pergeneral procedure F afforded after workup2-bromo-4-(2-{[4-(trifluoromethyl)benzyl]amino}ethyl)phenol, which wasused in the next step without further purification.

Step 3.

Alkylation of the above intermediate with ethyl-2-bromoisobutyrate asper general procedure C (2.2 eq NaH, THF, reflux, 15 hr) afforded afterchromatography the intermediate ethyl ester.

2-(4-{2-[[2,4-Bis(trifluoromethyl)benzyl](5-ethylpyrimidin-2-yl)amino]ethyl)phenoxy)-2-methylpropanoicAcid

Step 1.

Condensation of methyl2-[4-(2-{[2,4-bis(trifluoromethyl)benzyl]amino}ethyl)phenoxy]-2-methylpropanoate(250 mg; 0.54 mmol) with 2-chloro-5-ethyl-pyrimidine (230 mg; 1.62 mmol)as per general procedure E (conditions: 1 eq DIEA, toluene, 150C, 16 hr)provided after chromatography the intermediate methyl ester (117 mg; 38%yield).

Step 2.

Hydrolysis of the ester (117 mg) with NaOH as per general procedure Hprovided after chromatography the title compound as a glassy solid (55mg; 48% yield).

¹H NMR (CDCl₃) δ 8.22 (s, 2H), 7.85 (s, 1H), 7.61 (d, 2H, J=8.3), 7.31(d, 2H, J=8.3), 7.04 (d, 2H, J=8.5), 6.80 (d, 2H, J=8.5), 4.93 (s, 2H),3.72 (t, 2H, J=7.5), 2.85 (t, 2H, J=7.5), 2.47 (q, 2H, J=7.6), 1.53 (s,6H), 1.23 (t, 3H, J=7.6).

2-(4-{2-[[2,4-Bis(trifluoromethyl)benzyl](pyrimidin-2-yl)amino]ethylphenoxy)-2-methylpropanoicAcid

Step 1.

Condensation of methyl2-[4-(2-([2,4-bis(trifluoromethyl)benzyl]amino}ethyl)phenoxy]-2-methylpropanoate(200 mg; 0.43 mmol) with 2-chloro-pyrimidine (64 mg; 0.56 mmol) as pergeneral procedure E (conditions: 2 eq. DIEA, THF, 100C, 16 hr) providedafter chromatography the intermediate methyl ester (17 mg; 8% yield).MS: m/z 542 (M+1).

Step 2.

Hydrolysis of the methyl ester (17 mg) with NaOH as per generalprocedure H provided after chromatography and crystallization fromdichloromethane-hexane, the title compound as a white solid (10 mg; 58%yield).

¹H NMR (CDCl₃) δ 8.36 (d, 2H, J=4.7), 7.88 (s, 1H), 7.64 (d, 1H, J=8.1),7.32 (d, 1H, J=8.1), 7.08 (d, 2H, J=8.4), 6.83 (d, 2H, J=8.4), 6.59 (t,1H, J=4.7), 4.96 (s, 2H), 3.77 (t, 2H, J=7.5), 2.90 (t, 2H, J=7.5), 1.54(s, 6H).

2-(4-{2-[[2,4-Bis(trifluoromethyl)benzyl](5-propylpyrimidin-2-yl)amino]ethyl}phenoxy)-2-methylpropanoicAcid

Condensation of methyl2-[4-(2-{[2,4-bis(trifluoromethyl)benzyl]amino}ethyl)phenoxy]-2-methylpropanoate(250 mg; 0.54 mmol) with 2-chloro-5-propyl-pyrimidine (85 mg; 0.54 mmol)as per general procedure E (1.25 eq. K2CO3, dioxane, 220C, 15 hr) wasaccompanied by partial ester hydrolysis and afforded the title compoundin low yield. For ease of purification, the carboxylic acid wasconverted to its methyl ester derivative (using a standardtrimethylsilyldiazomethane/MeOH protocol), chromatographed and subjectedto the base-mediated hydrolysis procedure H to afford the title compoundin 17% yield (29 mg).

¹H NMR (CDCl₃) δ 8.20 (s, 2H), 7.85 (s, 1H), 7.62(d, 1H, J=8.2), 7.32(d, 1H, J=8.2), 7.04 (d, 1H, J=8.1), 6.80 (d, 1H, J=8.1), 4.93 (s, 2H),3.72 (t, 2H, J=7.4), 2.86 (t, 2H, J=7.4), 2.40 (t, 2H, J=7.6), 1.58 (m,2H), 1.53 (s, 6H), 0.93 (t, 3H, J=7.6).

2-(3-{3-[[2,4-Bis(trifluoromethyl)benzyl](pyrimidin-2-yl)amino]propyl}phenoxy)-2-methylpropanoicAcid

Step 1.

Condensation of tert-butyl2-[3-(3-{[2,4-bis(trifluoromethyl)benzyl]amino}propyl)phenoxy]-2-methylpropanoate(200 mg; 0.39 mmol) with 2-chloro-pyrimidine (133 mg; 1.16 mmol) as pergeneral procedure E (conditions: 3 eq DIEA, dioxane, 120C, 72 hr)provided the intermediate ester (110 mg; 48% yield). MS: m/z 598 (M+1).

Step 2.

Hydrolysis of the above tert-butyl ester (110 mg) with TFA as pergeneral procedure I provided after chromatography the title compound asa glassy solid (54 mg; 55% yield).

¹H NMR (CDCl₃) δ 8.32 (d, 2H, J=4.7), 7.88 (s, 1H), 7.64 (d, 1H, J=8.1),7.30 (d, 1H, J=8.1), 7.11 (t, 1H, J=7.8), 6.79(d, 1H, J=7.8), 6.76 (bs,1H), 6.71(dd, 1H, J=7.8; 2.2), 6.56 (t, 1H, J=4.7), 5.06 (s, 2H), 3.55(t, 2H, J=7.6), 2.57 (t, 2H, J=7.6), 1.91 (m, 2H), 1.57 (s, 6H).

2-[4-(2-{[2,4-bis(trifluoromethyl)benzyl][4-(trifluoromethyl)pyrimidin-2-yl]amino}ethyl)phenoxy]-2-methylpropanoicAcid

Step 1.

Condensation of methyl2-[4-(2-{[2,4-bis(trifluoromethyl)benzyl]amino}ethyl)phenoxy]-2-methylpropanoate(250 mg; 0.54 mmol) with 2-chloro-4-trifluoromethyl-pyrimidine (108 mg;0.59 mmol) as per general procedure E (conditions: 1.1 eq. DIEA,toluene, 170C, 16 hr) provided the intermediate ester (300 mg; 83%yield). MS: m/z 610 (M+1).

Step 2.

Hydrolysis of the methyl ester (300 mg) with NaOH as per generalprocedure H provided after chromatography and crystallization fromdichloromethane-hexane, the title compound as a white solid (191 mg; 65%yield).

¹H NMR (CDCl₃) δ 10.2 (bs, 1H), 8.60 (broad d, 1H), 7.90 (s, 1H), 7.65(d, 1H, J=8.1), 7.33 (d, 1H, J=8.1), 7.08 (d, 2H, J=8.1), 6.84 (m, 3H),5.02 (s, 2H), 3.79 (t, 2H, J=7.5), 2.90 (t, 2H, J=7.5), 1.55 (s, 6H).MS: m/z 596 (M+1).

2-(3-3-[[4-(5-Cyclopropyl-1,2,4-oxadiazol-3-yl)benzyl](pyrimidin-2-yl)amino]propyl}phenoxy)-2-methylpropanoicAcidStep 1. Condensation of tert-butyl2-[3-(3-{[4-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)benzyl]amino}propyl)phenoxy]-2-methylpropanoate(100 mg; 0.20 mmol) with 2-chloro-pyrimidine (26 mg; 0.22 mmol) as pergeneral procedure E (conditions: 1.1 eq DIEA, dioxane, 180C, 16 hr)provided the intermediate ester (76 mg; 66% yield).

Step 2.

Hydrolysis of the tert-butyl ester (76 mg) with TFA as per generalprocedure I provided after radial chromatography and crystallizationfrom hexane, the title compound as a white solid (25 mg; 36% yield).

¹H NMR (CDCl₃) δ 8.31 (d, 2H, J=4.7), 7.88 (d, 2H, J=8.2), 7.23 (d, 2H,J=8.2), 7.10 (t, 1H, J=7.8), 6.77 (d, 1H, J=7.8), 6.70 (m, 2H), 6.51 (t,1H, J=4.7), 4.86 (s, 2H), 3.53 (t, 2H, J=7.6), 2.53 (t, 2H, J=7.6), 2.23(m, 1H), 1.83 (m, 2H), 1.56 (s, 6H), 1.28 (m, 4H). MS: m/z 514 (M+1).

2-[4-(2-{(5-Ethylpyrimidin-2-yl)[4-(trifluoromethoxy)benzyl]amino}ethyl)phenoxy]-2-methylpropanoicAcid

Step 1.

Condensation of ethyl2-methyl-2-[4-(2-{[4-(trifluoromethoxy)benzyl]amino}ethyl)phenoxy]propanoate(1.20 g; 2.82 mmol) with 2-chloro-5-ethyl-pyrimidine (0.38 g; 2.64 mmol)as per general procedure E (conditions: 1.1 eq DIEA, toluene, 210C, 16hr) provided after chromatography the intermediate ester (900 mg; 64%yield).

Step 2.

Hydrolysis of the ethyl ester (900 mg) with NaOH as per generalprocedure H provided after chromatography the title compound as a glassysolid (680 mg; 79% yield). ¹H NMR (CDCl₃) δ 1.20 (t, 3H, J=7.7); 1.54(s, 6H); 2.44 (q, 2H, J=7.3); 2.80 (t, 2H, J=7.7); 3.69 (t, 2H, J=7.7);4.70 (s, 2H); 6.82 (d, 2H, J=8); 7.05 (d, 2H, J=8.9); 7.16 (d, 2H,J=8.6); 7.36 (d, 2H, J=8.3), 8.21 (s, 2H). Anal. Calcd. ForC₂₆F₂₈F₃N₃O₄: C, 62.02; H, 5.61; N, 8.35. Found C, 61.81; H, 5.74; N,8.06. MS: m/z 504 (M+1).

2-[4-(2-{(5-Ethylpyrimidin-2-yl)[4-(trifluoromethyl)benzyl]amino}ethyl)phenoxy]-2-methylpropanoicAcid

Step 1.

Condensation of ethyl2-methyl-2-[4-(2-([4-(trifluoromethyl)benzyl]amino}ethyl)phenoxy]propanoate(200 mg; 0.49 mmol) with 2-chloro-5-ethyl-pyrimidine (77 mg; 0.54 mmol)as per general procedure E (conditions: 1.1 eq DIEA, toluene, 205C, 16hr) provided after chromatography the intermediate ester (110 mg; 43%yield). MS: m/z 516 (M+1).

Step 2.

Hydrolysis of the ethyl ester (110 mg) with NaOH as per generalprocedure H provided after chromatography the title compound as a glassysolid (64 mg; 61% yield). ¹H NMR (CDCl₃) δ 8.23 (s, 2H), 7.47 (d, 2H,J=8.0), 7.22 (d, 2H, J=8.0), 7.02 (d, 2H, J=8.3), 6.79 (d, 2H, J=8.3),4.71 (s, 2H), 3.72 (t, 2H, J=7.3), 2.80 (t, 2H, J=7.3), 2.46 (q, 2H,J=7.6), 1.53 (s, 6H), 1.18 (t, 3H, J=7.6).

2-Methyl-2-[4-(2-{pyrimidin-2-yl[4-(trifluoromethyl)benzyl]amino}ethyl)phenoxy]propanoicAcid

Step 1.

Condensation of ethyl 2-methyl-2-[4-(2-{[4-5(trifluoromethyl)benzyl]amino}ethyl)phenoxy]propanoate (200 mg; 0.49mmol) with 2-chloro-pyrimidine (62 mg; 0.54 mmol) as per generalprocedure E (conditions: 1.1 eq DIEA, toluene, 205C, 16 hr) providedafter chromatography the intermediate ester (200 mg; 84% yield). MS: m/z488 (M+1).

Step 2.

Hydrolysis of the ethyl ester (200 mg) with NaOH as per generalprocedure H provided after chromatography the title compound as a glassysolid (112 mg; 58% yield). ¹H NMR (CDCl₃) δ 10.8 (broad s, 1H), 8.36 (d,2H, J=4.8), 7.48 (d, 2H, J=8.2), 7.24 (d, 2H, J=8.2), 7.03 (d, 2H,J=8.5), 6.81 (d, 2H, J=8.5), 6.54 (t, 1H, J=4.8), 4.74 (s, 2H), 3.74 (t,2H, J=7.5), 2.81 (t, 2H, J=7.5), 1.54 (s, 6H).

2-[4-(2-{(5-Chloropyrimidin-2-yl)[4-(trifluoromethyl)benzyl]amino}ethyl)phenoxy]-2methylpropanoic Acid

Step 1.

Condensation of ethyl2-methyl-2-[4-(2-{[4-(trifluoromethyl)benzyl]amino}ethyl)phenoxy]propanoate(200 mg; 0.49 mmol) with 2,5-20 dichloro-pyrimidine (70 mg; 0.46 mmol;prepared as in Liebigs Ann. Chem. 1985, p. 316) as per general procedureE (conditions: 2 eq DIEA, dioxane, 205C, 15 hr) provided theintermediateester (195 mg; 77% yield). MS: m/z 522 (M+1).

Step 2. Hydrolysis of the ethyl ester (200 mg) with NaOH as per generalprocedure H provided after chromatography the title compound as a glassysolid (90 mg; 65% yield). ¹H NMR (CDCl₃) δ 8.25 (s, 2H), 7.50 (d, 2H,J=8.1), 7.24 (d, 2H, J=8.1), 7.04 (d, 2H, J=8.5), 6.83 (d, 2H, J=8.5),4.72 (s, 2H), 3.73 (t, 2H, J=7.5), 2.83 (t, 2H, J=7.5), 1.56 (s, 6H).MS: m/z 492 (M−1).

2-[4-(2-{(5-Bromopyrimidin-2-yl)[4-(trifluoromethyl)benzyl]amino}ethyl)phenoxy]-2-methylpropanoicAcid

Step 1.

Condensation of ethyl2-methyl-2-[4-(2-{[4-(trifluoromethyl)benzyl]amino}ethyl)phenoxy]propanoate(5.16 g; 12.6 mmol) with 2,5-dibromo-pyrimidine (3.0 g; 10.5 mmol) asper general procedure E (conditions: 1.1 eq DIEA, 210C, 2 hr) providedafter chromatography the intermediate ethyl2-[4-(2-{(5-bromopyrimidin-2-yl)[4-(trifluoromethyl)benzyl]amino}ethyl)phenoxy]-2-methylpropanoate(2.2 g; 37% yield).

Step 2.

Hydrolysis of the ethyl ester with LiOH as per general procedureprovided after workup the title compound in good yield.

¹H NMR (CDCl₃) δ 8.39 (s, 2H), 7.60 (d, 2H, J=8.1), 7.39 (d, 2H, J=8.0),7.08 (d, 2H, J=8.4), 6.84 (d, 2H, J=8.4), 4.81 (s, 2H), 3.80 (t, 2H,J=7.2), 2.87 (t, 2H, J=7.2), 1.54 (s, 6H).

2-[4-(2-{(5-Cyanopyrimidin-2-yl)[4-(trifluoromethyl)benzyl]amino}ethyl)phenoxy]-2-methylpropanoicAcid

Step 1.

Ethyl2-[4-(2-{(5-bromopyrimidin-2-yl)[4-(trifluoromethyl)benzyl]amino}ethyl)phenoxy]-2-methylpropanoate,(100 mg; 0.18 mmol) wasreacted with CuCN (21 mg; 0.23 mmol) in 0.88 mlof DMF at 145C for 14 hours. The reaction mixture was diluted with waterand extracted with ethyl acetate. The organic layer was dried oversodium sulfate, filtered and concentrated. Purification by flashchromatography on silica gel using 20% ethyl acetate in hexanes providedthe intermediate ester (35 mg; 39% yield).

Step 2.

Hydrolysis of the ethyl ester with LiOH as per general procedure Hprovided after workup the title compound in good yield.

¹H NMR (CD₃OD) δ 8.83 (s, 2H), 7.62 (d, 2H, J=8.1), 7.42 (d, 2H, J=8.0),7.11 (d, 2H, J=8.4), 6.85 (d, 2H, J=8.5), 4.92 (s, 2H), 3.90 (t, 2H,J=7.0), 2.91 (t, 2H, J=7.1), 1.55 (s, 6H). MS: m/z 503 (M+1).

2-(4-{2-[(5-Ethylpyrimidin-2-yl)(pyridin-3-ylmethyl)amino]ethyl}phenoxy)-2-methylpropanoicAcid

Step 1.

Condensation of ethyl2-methyl-2-(4-{2-[(pyridin-3-ylmethyl)amino]ethyl}phenoxy)propanoate(255 mg; 0.75 mmol) with 2-chloro-5-ethyl-pyrimidine (105 mg; 0.75 mmol)as per general procedure E (conditions: 1 eq DIEA, toluene, 100 C, 16hr) provided the intermediate ester (31 mg; 9% yield).

Step 2.

Hydrolysis of the ethyl ester (31 mg) with LiOH as per general procedureH provided the title compound as a glassy solid (7 mg; 25% yield).

2-(4-{2-[(5-isopropylpyrimidin-2-yl)(pyridin-3-ylmethyl)amino]ethyl}phenoxy)-2-methylpropanoicAcid

Step 1.

Condensation of ethyl2-methyl-2-(4-{2-[(pyridin-3-ylmethyl)amino]ethyl}phenoxy)propanoate(231 mg; 0.75 mmol) with 2-chloro-5-isopropyl-pyrimidine (106 mg; 0.68mmol) as per general procedure E (conditions: 2.5 eq DIEA, toluene,110C, 16 hr) provided the intermediate ester (36 mg; 12% yield).

Step 2.

Hydrolysis of the ethyl ester (36 mg) with LiOH as per general procedureH provided the title compound (19 mg; 56% yield).

2-(4-{2-[(5-Ethylpyrimidin-2-yl)(pyridin-4-ylmethyl)amino]ethyl}phenoxy)-2-methylpropanoicAcid

Step 1.

Condensation of ethyl2-methyl-2-(4-{2-[(pyridin-4-ylmethyl)amino]ethyl}phenoxy)propanoate(369 mg; 1.08 mmol) with 2-chloro-5-ethyl-pyrimidine (153 mg; 1.08 mmol)as per general procedure E (conditions: 2.2 eq DIEA, toluene, 110 C, 16hr) provided the intermediate ester (19 mg; 4% yield)

Step 2.

Hydrolysis of the ethyl ester (19 mg) with LiOH as per general procedureH provided the title compound as a light brown oil (10 mg; 54% yield).

2-[4-(2-{(5-Ethylpyrimidin-2-yl)[4-(trifluoromethyl)benzyl]amino}ethyl)-2-methoxyphenoxy]-2-methylpropanoicAcid

Step 1.

Condensation of ethyl2-[2-methoxy-4-(2-{[4-(trifluoromethyl)benzyl]amino}ethyl)phenoxy]-2-methylpropanoate(500 mg; 1.14 mmol) with 2-chloro-5-ethyl-pyrimidine (178 mg; 1.25 mmol)as per general procedure E (conditions: 1.2 eq DIEA, toluene, 200C, 16hr) provided the intermediate ester (142 mg; 26% yield).

Step 2.

Hydrolysis of the ethyl ester (142 mg) with LiOH as per generalprocedure H provided the title compound as a glassy solid (118 mg; 88%yield).

¹H NMR (CDCl₃) δ 8.18 (s, 2H), 7.49 (d, 2H, J=8.1), 7.25 (d, 2H, J=8.1),6.86 (d, 1H, J=7.9), 6.64-6.72 (m, 2H), 4.76 (s, 2H), 3.80 (s, 3H), 3.77(t, 2H, J=7.5), 2.85 (t, 2H, J=7.7), 2.45 (q, 2H, J=7.7), 1.45 (s, 6H),1.18 (t, 3H, J=7.7).

2-[2-Bromo-4-(2-{(5-ethylpyrimidin-2-yl)[4-(trifluoromethyl)benzyl]amino}ethyl)phenoxy]-2-methylpropanoicAcid

Step 1.

Condensation of ethyl2-[2-bromo-4-(2-{[4-(trifluoromethyl)benzyl]amino}ethyl)phenoxy]-2-methylpropanoate(500 mg; 1.02 mmol) with 2-chloro-5-ethyl-pyrimidine (1 eq) as pergeneral procedure E (conditions: 1.1 eq DIEA, toluene, 200C, 14 hr)provided the intermediate ethyl2-[2-bromo-4-(2-{(5-ethylpyrimidin-2-yl)[4-(trifluoromethyl)benzyl]amino}ethyl)phenoxy]-2-methylpropanoate(134 mg; 23% yield).

Step 2.

Hydrolysis of the ethyl ester with LiOH as per procedure H provided thetitle compound as a beige solid.

¹H NMR (CDCl₃) δ 8.20 (s, 2H), 7.49 (d, 2H, J=8.1), 7.36 (d, 1H, J=2.0),7.24 (d, 2H, J=8.1), 6.97 (dd, 1H, J=8.4, 2.0), 6.88 (d, 1H. J=8.2),4.77 (s, 2H), 3.72 (t, 2H, J=7.9), 2.79 (t, 2H, J=7.3), 2.46 (q, 2H,J=7.7), 1.57 (s, 6H), 1.18 (t, 3H, J=7.7). MS: m/z 566, 568 (M+1).

2-[2Cyano-4-(2-{(5-ethylpyrimidin-2-yl)[4-(trifluoromethyl)benzyl]amino}ethyl)phenoxy]-2-methylpropanoicAcid

Step 1.

A solution of ethyl2-[2-bromo-4-(2-{(5-ethylpyrimidin-2-yl)[4-(trifluoromethyl)benzyl]amino}ethyl)phenoxy]-2-methylpropanoate(from step 1 in the previous example) (188 mg; 0.32 mmol) in DMF (2 ml)was treated with CuCN (37 mg; 0.41 mmol) and heated to reflux overnightunder a nitrogen atmosphere. Upon cooling, the reaction mixture wasfiltered through a plug of silica gel and eluted with DMF. The filtratewas concentrated and partitioned between dichloromethane and brine. Theorganic phase was dried over MgSO₄, filtered and concentrated to affordethyl2-[2-cyano-4-(2-{(5-ethylpyrimidin-2-yl)[4-(trifluoromethyl)benzyl]amino}ethyl)phenoxy]-2-methylpropanoate(153 mg), which was used in the next step without further purification.

Step 2.

Hydrolysis of the ethyl ester with LiOH as per general procedure Hprovided the title compound.

¹H NMR (CDCl₃) δ 8.21 (s, 2H), 7.48 (d, 2H, J=8.2), 7.33 (s, 1H), 7.23(d, 2H, J=8.2), 7.17 (d, 1H, J=8.2), 6.77 (d, 1H, J=8.2), 4.78 (s, 2H),3.78 (t, 2H, J=7.5), 2.77 (t, 2H, J=7.4), 2.46 (q, 2H, J=7.6), 1.60 (s,6H), 1.18 (t, 3H, J=7.5). MS: m/z 513 (M+1).

4-{2-[(5-Ethylpyrimidin-2-yl)amino]ethyl}phenol

Tyramine (5.52 g, 0.040 mol) in 40 ml of anhydrous DMF was treated withdiisopropylethylamine (6.1 ml, 0.035 mol). After stirring at rt for 15minutes, 2-chloro-5-ethylpyrimidine (4.25 ml, 0.035 mol) was added andthe mixture heated at 80° C. for 14 hours. The solution was allowed tocool to room temperature and was partitioned between equal volumes ofwater and ethyl acetate. The aqueous phase was washed with ethyl acetateand the combined organic phases were dried over MgSO₄ and concentrated.The residue was purified by flash chromatography eluting with 40% ethylacetate-hexane to afford the title compound as a colorless solid (4.94g; 58% yield).

¹H NMR (CDCl₃) δ 1.20 (t, 3H, J=7.6); 2.46 (q, 2H, J=7.6); 2.83 (t, 2H,J=6.3); 3.515 (s, 1H); 3.63 (q, 2H, J=6.3); 5.14 (brs, 1H); 6.70 (d, 2H,J=8.4); 7.02 (d, 2H, J=8.3), 8.19 (s, 2H). MS: m/z 244 (M+1).

Ethyl2-(4-{2-[(5-ethylpyrimidin-2-yl)amino]ethyl}phenoxy)-2-methylpropanoate

Alkylation of 4-{2-[(5-ethylpyrimidin-2-yl)amino]ethyl}phenol with 2 eqof ethyl 2-bromoisobutyrate as per general procedure C (conditions: 2 eqCs₂CO₃, MeCN, 80C, 4 hr) provided the title compound (80% yield).

¹H NMR (CDCl₃) δ 1.19 (t, 3H, J=7.5); 1.26 (t, 3H, J=7.1); 1.60 (s, 6H);2.45 (q, 2H, J=7.6); 2.84 (t, 2H, J=6.9); 3.62 (q, 2H, J=6.5); 4.23 (q,2H, J=7.2); 5.00 (s, 2H); 6.80 (d, 2H, J=8.4); 7.11 (d, 2H, J=8.4), and8.16 (s, 2H). MS: m/z 358 (M+1).

General Procedure for N-alkylation of the Intermediate Ethyl2-(4-{2-[(5-ethylpyrimidin-2-yl)amino]ethyl}phenoxy)-2-methylpropanoatewith Chloride or Bromide Reagents.

A solution of ethyl2-(4-{2-[(5-ethylpyrimidin-2-yl)amino]ethyl}phenoxy)-2-methylpropanoatein DMF (0.1-0.5 M) was treated with 1.1-1.5 eq of a base (NaH orNaHMDS). After stirring for 5 minutes, 1-1.5 eq of an appropriatechloride or bromide reagent was added and the mixture heated at 40-80Cfor 14 hours. Cooled to rt and partitioned between equal volumes ofethyl acetate and water. The organic phase was washed with brine, driedover MgSO₄ and concentrated. Purification by silica gel chromatographyeluting with 20% ethyl acetate-hexane afforded the desired N-alkylatedproduct in variable yields.

2-(4-{2-[(4-tert-Butylbenzyl)(5-ethylpyrimidin-2-yl)amino]ethyl}phenoxy)-2-methylpropanoicAcid

Step 1.

Alkylation of ethyl2-(4-{2-[(5-ethylpyrimidin-2-yl)amino]ethyl}phenoxy)-2-methylpropanoate(85 mg; 0.24 mmol) with 4-(tert-butyl)benzyl bromide (1 eq) as per thegeneral N-alkylation procedure above (1.1 eq NaH, 40C) afforded theintermediate ester (46 mg; 38% yield).

Step 2.

Hydrolysis of the ethyl ester with LiOH as per general procedure Hprovided the title compound in low overall yield.

¹H NMR (CDCl₃) δ 1.20 (t, 3H, J=7.7); 1.26 (t, 3H, J=7.7); 1.55 (s, 6H);2.46 (t, 2H, J=7.5); 2.83 (t, 2H, J=7); 3.73 (t, 2H, J=7.3); 4.21 (q,2H, J=7); 4.65 (s, 2H); 6.70 (s, 2H); 6.72 (s, 2H); 7.05 (s, 2H), 8.18(s, 2H).

2-[4-(2-{(5-Ethylpyrimidin-2-yl)[3-(trifluoromethoxy)benzyl]amino}ethyl)phenoxy]-2-methylpropanoicAcid

Similarly prepared by alkylation with 3-trifluoromethoxybenzyl bromide.

¹H NMR (CDCl₃) δ 1.28 (t, 3H, J=7); 1.60 (s, 6H); 2.48 (q, 2H, J=7.6);2.85 (t, 2H, J=7.7); 3.76 (t, 2H, J=7.6); 4.76 (s, 2H); 6.79 (d, 2H,J=8.6); 7.08 (m, 4H); 7.29 (d, 2H, J=7.9), 8.25 (s, 2H). MS: m/z 504(M+1); anal. Calcd. For C₂₆H₂₈F₃N₃O₄: C, 62.02; H. 5.61; N, 8.35; FoundC, 61.93; H, 5.63; N, 8.17.

2-{4-[2-((5-Ethylpyrimidin-2-yl){4-[(trifluoromethyl)thio]benzyl}amino)ethyl]phenoxy}-2-methylpropanoicAcid

Similarly prepared by alkylation with 4-trifluoromethylthio-benzylbromide.

¹H NMR (CDCl₃) δ 1.25 (t, 3H, J=7.4); 1.60 (s, 6H); 2.55 (q, 2H, J=7.4);2.93 (t, 2H, J=7.2); 3.93 (br t, 2H); 4.81 (s, 2H); 6.89 (d, 2H, J=8.3);7.14 (d, 2H, J=8.2); 7.60 (d, 4H, J=8.0); 8.36 (s, 2H). MS: m/z 520(M+1).

2-[4-(2-{(5-Ethylpyrimidin-2-yl)[4-(methylsulfonyl)benzyl]amino}ethyl)phenoxy]-2-methylpropanoicAcid

Similarly prepared by alkylation with 4-methylsulfone-benzyl bromide.

¹H NMR (CDCl₃) δ 1.19 (t, 3H, J=7.6); 1.29 (s, 3H); 1.60 (s, 6H); 2.54(q, 2H, J=7.6); 2.94 (t, 2H, J=7); 3.91 (br t, 2H); 4.81 (s, 2H); 6.89(d, 2H, J=8.2); 7.14 (d, 2H, J=8); 7.59 (d, 4H, J=7.9), and 8.34 (s,2H). MS: m/z 520 (M+Na).

2-[4-(2-{(5-Ethylpyrimidin-2-yl)[4-(methylthio)benzyl]amino}ethyl)phenoxy]-2-methylpropanoicAcid

Similarly prepared by alkylation with 4-methylthio-benzyl bromide.

¹H NMR (CDCl₃) δ 1.26 (t, 3H, J=7.6); 1.60 (s, 6H); 2.49 (s, 3H); 2.58(t, 2H, J=7.5); 2.77 (br t, 2H); 3.96 (br t, 2H); 4.76 (s, 2H); 6.89 (d,2H, J=8.3); 7.14 (m, 6H), and 8.39 (s, 2H). MS: m/z 466 (M+1).

2-(4-{2-[(5-Ethylpyrimidin-2-yl)(4-methoxybenzyl)amino]ethyl}phenoxy)-2-methylpropanoicAcid

Similarly prepared by alkylation with 4-methoxy-benzyl chloride.

¹H NMR (CDCl₃) δ 1.16 (t, 3H, J=7.6); 1.54 (s, 6H); 2.43 (q, 2H, J=7.5);2.73 (t, 2H, J=7.7); 3.65 (t, 2H, J=7.3); 3.73 (s, 3H); 4.64 (s, 2H);6.78 (dd, 4H, J=8, 5); 7.01 (d, 2H, J=8.2); 7.06 (d, 2H, J=8.5), and8.22 (s, 2H). MS: m/z 450 (M+1).

2-(4-{2-[(5-Ethylpyrimidin-2-yl)(3-furylmethyl)amino]ethyl}phenoxy)-2-methylpropanoicAcid

Similarly prepared by alkylation with chloromethyl-3-furan.

2-{4-[2-((5-Ethylpyrimidin-2-yl){3-[(trifluoromethyl)thio]benzyl}amino)ethyl]phenoxy)-2-methylpropanoicAcid

Similarly prepared by alkylation with 3-trifluoromethyl benzylbromide.

¹H NMR (CDCl₃) δ 1.21 (t, 3H, J=7.2); 1.54 (s, 6H); 2.44 (q, 2H, J=7.6);2.76 (t, 2H, J=7.7); 3.69 (t, 2H, J=7.4); 4.70 (s, 2H); 6.80 (d, 2H,J=8.4); 7.02 (d, 2H, J=8.3); 7.23 (dd, 2H, J=12; 7); 7.42 (s, 1H); 7.45(t, 1H, J=7), 8.22 (s, 2H).

2-(4-{2-[(3,5-Difluorobenzyl)(5-ethylpyrimidin-2-yl)amino]ethyl}phenoxy)-2-methylpropanoicAcid

Similarly prepared by alkylation with 3,5-difluoro-benzylbromide.

¹H NMR (CDCl₃) δ 1.26 (t, 3H, J=7.7); 1.61 (s, 6H); 2.56 (q, 2H, J=7.3);2.96 (br t, 2H); 3.96 (br t, 2H); 4.75 (s, 2H); 6.73 (d, 2H, J=7.1);6.88 (d, 2H, J=8.1); 7.15 (d, 3H, J=8.1), 8.38 (s, 2H). MS: m/z 456(M+1).

2-[4-(2-{(5-Ethylpyrimidin-2-yl)[4-fluoro-2-(trifluoromethyl)benzyl]amino}ethyl)phenoxy]-2-methylpropanoicAcid

Similarly prepared by alkylation with4-fluoro-2-trifluoromethyl-benzylbromide.

¹H NMR (CDCl₃) δ 1.25 (t, 3H, J=7.2); 1.59 (s, 6H); 2.59 (br q, 2H);2.99 (br t, 2H); 3.94 (br t, 2H); 4.99 (s, 2H); 6.85 (d, 2H, J=8); 7.17(d, 2H, J=7.7); 7.29 (s, 1H); 7.39 (d, 2H, J=8.7), 8.40 (s, 2H). MS: m/z506 (M+1).

2-(4-{2-[[3,5-Bis(trifluoromethyl)benzyl](5-ethylpyrimidin-2-yl)amino]ethyl}phenoxy)-2-methylpropanoicAcid.

Similarly prepared by alkylation with 3,5-bis-trifluoromethylbenzylbromide.

¹H NMR (CDCl₃) δ 1.24 (t, 3H, J=7.7); 1.60 (s, 6H); 2.51 (q, 2H, J=7.6);2.88 (t, 2H, J=7.3); 3.82 (t, 2H, J=7); 4.83 (s, 2H); 6.88 (d, 2H,J=8.1); 7.12 (d, 2H, J=8.3); 7.65 (s, 2H); 7.77 (s, 1H); 8.28 (s, 2H).MS: m/z 556 (M+1)

2-(4-{2-[(4-Ethylbenzyl)(5-ethylpyrimidin-2-yl)amino]ethyl}phenoxy)-2-methylpropanoicAcid

Similarly prepared by alkylation with 4-ethyl-benzylbromide.

¹H NMR (CDCl₃) δ 1.21 (t, 3H, J=7.7); 1.26 (t, 3H, J=7.5); 1.59 (s, 6H);2.56 (q, 2H, J=7.3); 2.60 (q, 2H, J=7.6); 2.90 (br t, 2H); 3.90 (br t,2H); 4.78 (s, 2H); 6.85 (d, 2H, J=8); 7.12 (d, 4H, J=7), 8.37 (s, 2H).MS: m/z 448 (M+1).

2-(4-{2-[(4-Cyanobenzyl)(5-ethylpyrimidin-2-yl)amino]ethyl}phenoxy)-2-methylpropanoicacid

Similarly prepared by alkylation with 4-cyano-benzylbromide.

¹H NMR (CDCl₃) δ 1.21 (t, 3H, J=7.4); 1.60 (s, 6H); 2.55 (q, 2H, J=7.6);2.92 (t, 2H, J=6.6); 3.98 (br t, 2H); 4.83 (s, 2H); 6.84 (d, 2H, J=8.3);7.11 (d, 2H, J=8.3); 7.32 (d, 2H, J=8.2); 7.59 (d, 2H, J=8), and 8.38(s, 2H). MS: m/z 445 (M+1).

2-(4-{2-[(5-Ethylpyrimidin-2-yl)(3-methylbenzyl)amino]ethyl}phenoxy)-2-methylpropanoicAcid

Similarly prepared by alkylation with 3-methyl-benzylbromide.

¹H NMR (CDCl₃) δ 1.22 (t, 3H, J=7.5); 1.59 (s, 6H); 2.32 (s, 3H); 2.48(q, 2H, J=7.6); 2.82 (t, 2H, J=7.8); 3.74 (t, 2H, J=7.9); 4.75 (s, 2H);6.85 (d, 2H, J=8.5); 6.98 (d, 2H, J=8.2); 7.08 (d, 2H, J=8.4); 7.16 (d,1H, J=7.5); 7.21 (t, 1H, J=8.3), 8.28 (s, 2H). MS: m/z 434 (M+1).

2-(4-{2-[(2-Chloro-4-fluorobenzyl)(5-ethylpyrimidin-2-yl)amino]ethylphenoxy)-2-methylpropanoicAcid

Similarly prepared by alkylation with 2-chloro-4-fluoro-benzylbromide.

¹H NMR (CDCl₃) δ 1.17 (t, 3H, J=7.4); 1.60 (s, 6H); 2.42 (q, 2H, J=7.9);2.80 (t, 2H, J=7.2); 3.70 (t, 2H, J=7.3); 4.77 (s, 2H); 6.70 (d, 2H,J=6.6); 6.82 (d, 2H, J=8.4); 6.92 (d, 1H, J=7.8); 7.05 (d, 1H, J=8.3);7.06 (s, 1H), 8.18 (s, 2H). MS: m/z 472 (M+1)

2-(4-{2-[(4-Bromobenzyl)(5-ethylpyrimidin-2-yl)amino]ethyl}phenoxy)-2-methylpropanoicAcid

Similarly prepared by alkylation with 4-bromo-benzylbromide.

¹H NMR (CDCl₃) δ 1.23 (t, 3H, J=7.6); 1.60 (s, 6H); 2.50 (q, 2H, J=7.6);2.85 (t, 2H, J=7.2); 3.77 (t, 2H, J=7.2); 4.71 (s, 2H); 6.86 (d, 2H,J=8.4); 7.07 (dd, 4H, J=11, 8); 7.41 (d, 2H, J=8.3), 8.29 (s, 2H).

2-(4-{2-[(2-Cyanobenzyl)(5-ethylpyrimidin-2-yl)amino]ethyl}phenoxy)-2-methylpropanoicAcid

Similarly prepared by alkylation with 2-cyano-benzylbromide.

¹H NMR (CDCl₃) δ 1.27 (t, 3H, J=7); 1.59 (s, 6H); 2.48 (q, 2H, J=7.6);2.88 (t, 2H, J=7.4); 3.79 (t, 2H, J=7.8); 5.05 (s, 2H); 6.77 (d, 2H,J=8.4); 7.12 (d, 2H, J=8.6); 7.32 (t, 1H, J=7.6); 7.42 (t, 1H, J=8.4);7.47 (d, 1H, J=7.8); 7.7 (d, 1H, J=7.5), 8.24 (s, 2H). MS: m/z 445(M+1).

2-(4-{2-[(5-ethylpyrimidin-2-yl)(2-methylbenzyl)amino]ethyl}phenoxy)-2-methylpropanoicAcid

Similarly prepared by alkylation with 2-methyl-benzylbromide.

¹H NMR (CDCl₃) δ 1.23 (t, 3H, J=7.6); 1.59 (s, 6H); 2.24 (s, 3H); 2.50(q, 2H, J=7.6); 2.84 (t, 2H, J=7.5); 3.76 (t, 2H, J=7.6); 4.74 (s, 2H);6.84 (d, 2H, J=8.4); 7.07 (d, 2H, J=8.4); 7.14 (m, 4H), 8.31 (s, 2H).MS: m/z 434 (M+1).

2-(4-{2-[(3,4-Dichlorobenzyl)(5-ethylpyrimidin-2-yl)amino]ethyl}phenoxy)-2-methylpropanoicAcid

Similarly prepared by alkylation with 3,4-dichloro-benzylbromide.

¹H NMR (CDCl₃) δ 1.23 (t, 3H, J=7.7); 1.60 (s, 6H); 2.50 (q, 2H, J=7.4);2.85 (t, 2H, J=7.2); 3.77 (t, 2H, J=7.1); 4.68 (s, 2H); 6.86 (d, 2H,J=8.4); 7.09 (d, 2H, J=8.4); 7.27 (d, 1H, J=7); 7.34 (d, 1H, J=8.2);7.45 (t, 1H, J=8.5), 8.29 (s, 2H). MS: m/z 488 (M+1).

2-(4-{(2-[(1,1′-Biphenyl-2-ylmethyl)(5-ethylpyrimidin-2-yl)amino]ethyl}phenoxy)-2-methylpropanoicAcid

Similarly prepared by alkylation with 2-phenyl-benzylbromide.

¹H NMR (CDCl₃) δ 1.17 (t, 3H, J=7.4); 1.51 (s, 6H); 2.44 (q, 2H, J=7.5);2.61 (t, 2H, J=6.9); 3.56 (br t, 2H); 4.60 (s, 2H); 6.71 (d, 2H, J=8.3);6.88 (d, 2H, J=7.7); 7.35 (m, 9H), 8.19 (s, 2H). MS: m/z 496 (M+1).

2-(4-{2-[(4-chlorobenzyl)(5-ethylpyrimidin-2-yl)amino]ethyl}phenoxy)-2-methylpropanoicAcid

Similarly prepared by alkylation with 4-chloro-benzylbromide.

¹H NMR (CDCl₃) δ 1.25 (t, 3H, J=7.7); 1.60 (s, 6H); 2.58 (t, 2H, J=7.6);2.92 (6.8); 4.00 (t, 2H, J=6.5); 4.79 (s, 2H); 6.84 (d, 2H, J=8.3); 7.14(d, 4H, J=7.9), 8.45 (s, 2H). MS: m/z 454 (M+1).

2-(4-{2-[Benzyl(5-ethylpyrimidin-2-yl)amino]ethyl}phenoxy)-2-methylpropanoicAcid

Similarly prepared by alkylation with benzylbromide.

¹H NMR (CDCl₃) δ 1.23 (t, 3H, J=7.6); 1.59 (s, 6H); 2.49 (q, 2H, J=7.6);2.83 (t, 2H, J=7.6); 3.77 (t, 2H, J=7.3); 4.79 (s, 2H); 6.88 (d, 2H,J=8.2); 7.09 (d, 2H, J=8.4); 7.19 (d, 4H, J=7.6); 7.29 (t, 1H, J=7.1),8.30 (s, 2H). MS: m/z 420 (M+1).

2-[4-(2-{(5-Ethylpyrimidin-2-yl)[2-(trifluoromethoxy)benzyl]amino}ethyl)phenoxy]-2-methylpropanoicAcid

Similarly prepared by alkylation with 2-trifluoromethoxybenzyl bromide.

¹H NMR (CDCl₃) δ 1.22 (t, 3H, J=7.6); 1.59 (s, 6H); 2.45 (q, 2H, J=7.6);2.85 (t, 2H, J=7.7); 3.73 (t, 2H, J=7.6); 4.88 (s, 2H); 6.78 (d, 2H,J=8.4); 7.09 (d, 2H, J=6.5); 7.21 (dd, 4H, J=14; 6.5), 8.24 (s, 2H). MS:m/z 504 (M+1).

2-[4-(2-{(5-ethylpyrimidin-2-yl)[3-(trifluoromethyl)benzyl]amino}ethyl)phenoxy]-2-methylpropanoicAcid

Similarly prepared by alkylation with 3-trifluoromethyl-benzylbromide.

¹H NMR (CDCl₃) δ 1.23 (t, 3H, J=7.7); 1.60 (s, 6H); 2.50 (q, 2H, J=7.6);2.85 (t, 2H, J=7.6); 3.77 (t, 2H, J=7.1); 4.80 (s, 2H); 6.86 (d, 2H,J=8.4); 7.10 (d, 2H, J=8.4); 7.36 (s, 1H); 7.39 (d, 2H, J=7.4); 7.44 (t,1H, J=7.3), 8.28 (s, 2H).

2-[4-(2-{(5-Ethylpyrimidin-2-yl)[2-(trifluoromethyl)benzyl]amino}ethyl)phenoxy]-2-methylpropanoicAcid

Similarly prepared by alkylation with 2-trifluoromethyl-benzylbromide.

¹H NMR (CDCl₃) δ 1.22 (t, 3H, J=7.6); 1.58 (s, 6H); 2.49 (q, 2H, J=7.6);2.88 (t, 2H, J=7.2); 3.73 (t, 2H, J=7.3); 4.99 (s, 2H); 6.85 (d, 2H,J=8.4); 7.10 (d, 2H, J=8.3); 7.23 (qn, 2H); 7.41 (t, 1H, J=7.4); 7.65(d, 1 H, J=7.8), 8.27 (s, 2H). MS: m/z 488 (M+1).

2-(4-{2-[(5-Ethylpyrimidin-2-yl)(4-fluorobenzyl)amino]ethyl}phenoxy)-2-methylpropanoicAcid

Similarly prepared by alkylation with 4-fluoro-benzylbromide.

¹H NMR (CDCl₃) δ 1.22 (t, 3H, J=7.5); 1.59 (s, 6H); 2.48 (q, 2H, J=7.6);2.80 (t, 2H, J=7.7); 3.70 (t, 2H, J=7.3); 4.71 (s, 2H); 6.84 (d, 2H,J=8.4); 6.97 (dd, 2H, J=8.8); 7.13 (d, 2H, J=6); 7.15 (dd, 2H, J=9;6),8.27 (s, 2H). MS: m/z 438 (M+1).

2-(4-{2-[(3-Chlorobenzyl)(5-ethylpyrimidin-2-yl)amino]ethylophenoxy)-2-methylpropanoicAcid

Similarly prepared by alkylation with 3-chloro-benzylbromide.

¹H NMR (CDCl₃) δ 1.22 (t, 3H, J=7.6); 1.59 (s, 6H); 2.48 (q, 2H, J=7.6);2.83 (t, 2H, J=7.9); 3.74 (t, 2H, J=7.4); 4.70 (s, 2H); 6.85 (d, 2H,J=8.4); 7.08 (d, 2H, J=8.4); 7.23 (m, 3H); 7.31 (s, 1 H), 8.27 (s, 2H).

2-(4-{2-[(2,5-Dichlorobenzyl)(5-ethylpyrimidin-2-yl)amino]ethyl}phenoxy)-2-methylpropanoicAcid

Similarly prepared by alkylation with 2,5-dichloro-benzylbromide.

2-(4-{2-[(5-Ethylpyrimidin-2-yl)(4-isopropylbenzyl)amino]ethyl}phenoxy)-2-methylpropanoicAcid

Similarly prepared by alkylation with 4-isopropyl-benzyl chloride.

2-(4-{2-[(2-Chlorobenzyl)(5-ethylpyrimidin-2-yl)amino]ethyl}phenoxy)-2-methylpropanoicAcid

Similarly prepared by alkylation with 2-chloro-benzyl bromide.

2-(4-{2-[(3,5-Dimethylbenzyl)(5-ethylpyrimidin-2-yl)amino]ethyl}phenoxy)-2-methylpropanoicAcid

Similarly prepared by alkylation with 3,5dimethyl-benzyl bromide.

2-(4-{2-[(5-Ethylpyrimidin-2-yl)(4-methoxy-3-methylbenzyl)amino]ethyl}phenoxy)-2-10methylpropanoic Acid

Similarly prepared by alkylation with 3-methyl-4-methoxy-benzylchloride.

2-(4-{2-[(5-Ethylpyrimidin-2-yl)(4-methylbenzyl)amino]ethyl}phenoxy)-2-methylpropanoicAcid

Similarly prepared by alkylation with 4-methyl-benzyl bromide.

2-(4-{2-[(5-Ethylpyrimidin-2-yl)(thien-2-ylmethyl)amino]ethyl}phenoxy)-2-methylpropanoicAcid

Similarly prepared by alkylation with 2-chloromethyl-thiophene.

2-{4-[2-((5-Ethylpyrimidin-2-yl){4-[(trifluoromethyl)sulfinyl]benzyl}amino)ethyl]phenoxy)-2-methylpropanoicAcid

Similarly prepared by alkylation with1-(bromomethyl)-4-[(trifluoromethyl)sulfinyl]benzene.

2-{4-[2-((5-Ethylpyrimidin-2-yl){4-[(trifluoromethyl)sulfonyl]benzyl}amino)ethyl]phenoxy}-2-methylpropanoicAcid

Similarly prepared by alkylation with1-(bromomethyl)-4-[(trifluoromethyl)sulfonyl]benzene.

2-[4-(2-{(5-Ethylpyrimidin-2-yl)[4-(trifluoromethoxy)benzyl]amino}ethyl)phenoxy]propanoicAcid

Step 1.

Alkylation of 4-{2-[(5-Ethylpyrimidin-2-yl)amino]ethyl}phenol (135 mg;0.56 mmol) with ethyl 2-bromopropionate (0.18 ml; 1.39 mmol) as pergeneral procedure C (conditions: 2 eq Cs2CO3, MeCN, 60C, 4 hr). providedethyl 2-(4-{2-[(5-ethylpyrimidin-2-yl)amino]ethyl}phenoxy)propanoate(143 mg; 75% yield).

Step 2-3.

In a two-step sequence similar to the previous example, alkylation ofthe above intermediate ethyl2-(4-{2-[(5-ethylpyrimidin-2-yl)amino]ethyl}phenoxy)propanoate with4-trifluoromethoxy-benzylbromide (1 eq) (1.5 eq NaH; 80C) followed byhydrolysis of the intermediate ester afforded the title compound.

4-(2-{(5-Ethylpyrimidin-2-yl)[4-(trifluoromethyl)benzyl]amino}ethyl)phenol

Condensation of 4-(2-{[4-(trifluoromethyl)benzyl]amino}ethyl)phenol(1.20 9; 4.06 mmol) with 2-chloro-5-ethyl-pyrimidine (0.52 ml; 4.27mmol) as per general procedure E (conditions: 1.1 eq. DIEA, toluene,210C, 16 hr) provided the title compound (1.40 9; 85% yield).

¹H NMR (CDCl₃) δ 8.20 (s, 2H), 7.98 (s, 1 H), 7.46 (d, 2H, J=8.2), 7.23(d, 2H, J=8.5), 6.97 (d, 2H, J=8.5), 6.70 (d, 2H, J=8.5), 4.75 (s, 2H),3.74 (t, 2H, J=7.3), 2.82 (t, 2H, J=7.3), 2.42 (q, 2H, J=7.5), 1.15 (t,3H, J=7.5).

[4-(2-{(5-Ethylpyrimidin-2-yl)[4-(trifluoromethyl)benzyl]amino}ethyl)phenoxy]aceticAcid

Step 1.

Alkylation of4-(2-{(5-ethylpyrimidin-2-yl)[4-(trifluoromethyl)benzyl]amino}ethyl)phenol(150 mg; 0.37 mmol) with t-butylbromoacetate (81 mg; 0.41 mmol) as pergeneral procedure C (1.1 eq. K₂CO₃, DMF, 80C, 18 hr) provided theintermediate tert-butyl ester (128mg; 67% yield).

Step 2.

Hydrolysis of the tert-butyl ester (128 mg) with TFA as per generalprocedure I provided after chromatography and crystallization fromdichloromethane-hexane, the title compound as a white solid (103 mg; 90%yield).

¹H NMR (CDCl₃) δ 8.24 (s, 2H), 7.50 (d, 2H, J=8.0), 7.25 (d, 2H, J=8.0),7.08 (d, 2H, J=8.6), 6.78 (d, 2H, J=8.6), 4.79 (s, 2H), 4.55 (s, 2H),3.75 (t, 2H, J=7.6), 2.84 (t, 2H, J=7.6), 2.48 (q, 2H, J=7.6), 1.19 (t,3H, J=7.6). MS: m/z 460 (M+1).

2-[4-(2-{(5-Ethylpyrimidin-2-yl)[4-(trifluoromethyl)benzyl]amino}ethyl)phenoxy]propanoicAcid

Similarly prepared from4-(2-{(5-ethylpyrimidin-2-yl)[4-(trifluoromethyl)benzyl]amino}ethyl)phenoland t-butyl 2-bromopropionate.

¹H NMR (CDCl₃) δ 8.24 (s, 2H), 7.48 (d, 2H, J=8.0), 7.22 (d, 2H, J=8.0),7.04 (d, 2H, J=8.5), 6.77 (d, 2H, J=8.5), 4.74 (s, 2H), 4.70 (q, 1 H,J=6.8), 3.69 (t, 2H, J=7.5), 2.77 (t, 2H, J=7.5), 2.46 (q, 2H, J=7.6),1.59 (d, 3H, J=6.8), 1.18 (t, 3H, J=7.6). MS: m/z 474 (M+1).

2-[4-(2-{(5-Ethylpyrimidin-2-yl)[4-(trifluoromethyl)benzyl]amino}ethyl)phenoxy]butanoicAcid

Similarly prepared from4-(2-{(5-ethylpyrimidin-2-yl)[4-(trifluoromethyl)benzyl]amino}ethyl)phenoland t-butyl 2-bromobutyrate.

¹H NMR (CDCl₃) δ 8.24 (s, 2H), 7.48 (d, 2H, J=8.0), 7.22 (d, 2H, J=8.0),7.04 (d, 2H, J=8.5), 6.77 (d, 2H, J=8.5), 4.74 (s, 2H), 4.52 (t, 1H,J=6.1), 3.69 (t, 2H, J=7.5), 2.76 (t, 2H, J=7.5), 2.46 (q, 2H, J=7.6),1.96 (m, 2H), 1.18 (t, 3H, J=7.6), 1.06 (t, 3H, J=7.4).

2-[4-(2-{(5-Ethylpyrimidin-2-yl)[4-(5-isopropyl-1,2,4-oxadiazol-3-yl)benzyl]amino}ethyl)phenoxy]-2-methylpropanoicAcid

Step 1.

Condensation of4-(2-{[4-(5-isopropyl-1,2,4-oxadiazol-3-yl)benzyl]amino}ethyl)phenol(400 mg; 1.19 mmol) with 2-chloro-5-ethyl-pyrimidine (178 mg; 1.25 mmol)as per general procedure E (conditions: 1.1 eq. DIEA, toluene, 210C, 16hr) provided the intermediate phenol (200 mg; 38% yield). MS: m/z 444(M+1).

Step 2. Alkylation of the above intermediate (125 mg; 0.28 mmol) with2-trichloromethyl-2-propanol (65 mg; 0.37 mmol) as per general procedureD provided after chromatography and crystallization fromdichloromethane-hexane, the title compound as a white solid (89 mg; 60%yield).

¹H NMR (CDCl₃) δ 8.22 (s, 2H), 7.90(d, 2H, J=8.1), 7.18 (d, 2H, J=8.1),6.98 (d, 2H, J=8.5), 6.76 (d, 2H, J=8.5), 4.73 (s, 2H), 3.73 (t, 2H,J=7.5), 3.25 (m, 1H), 2.78 (t, 2H, J=7.5), 2.46 (q, 2H, J=7.6), 1.54 (s,6H), 1.40 (d, 6H, J=7.1), 1.18 (t, 3H, J=7.6).

4-(2-{(5-Ethylpyrimidin-2-yl)[4-(trifluoromethoxy)benzyl]amino}ethyl)phenol

Condensation of 4-(2-[4-(trifluoromethoxy)benzyl]amino}ethyl)phenol (500mg; 1.61 mmol) with 2-chloro-5-ethyl-pyrimidine (0.19 ml; 1.54 mmol) asper general procedure E (conditions: 5 ml of DIEA, 200C, 16 hr) providedthe title compound (490 mg; 76% yield).

¹H NMR (CDCl₃) δ 8.25 (s, 2H), 7.84(bs, 1H), 7.19 (d, 2H, J=8.5), 7.10(d, 2H, J=8.5), 7.01 (d, 2H, J=8.4), 6.71 (d, 2H, J=8.4), 4.73 (s, 2H),3.77 (t, 2H, J=7.6), 2.85 (t, 2H, J=7.6), 2.48 (q, 2H, J=7.5), 1.21 (t,3H, J=7.5).

[4-(2-{(5-Ethylpyrimidin-2-yl)[4-(trifluoromethoxy)benzyl]amino}ethyl)phenoxy]aceticAcid

Step 1.

Alkylation of4-(2-{(5-ethylpyrimidin-2-yl)[4-(trifluoromethoxy)benzyl]amino}ethyl)phenol(125 mg; 0.30 mmol) with t-butyl bromoacetate (79 mg; 0.41 mmol) as pergeneral procedure C (1.35 eq. Cs2CO3, MeCN, 85C, 3 hr) provided theintermediate tert-butyl ester (130 mg; 81% yield).

MS: m/z 532 (M+1).

Step 2.

Hydrolysis of the tert-butyl ester (150 mg) with TFA as per generalprocedure I provided after chromatography and crystallization fromdichloromethane-hexane, the title compound as a white solid (107 mg; 90%yield).

¹H NMR (CDCl₃) δ 8.37 (s, 2H), 7.19 (d, 2H, J=8.5), 7.12 (d, 2H, J=8.5),7.07 (d, 2H, J=7.9), 6.78 (d, 2H, J=7.9), 4.76 (s, 2H), 4.55 (s, 2H),3.78 (t, 2H, J=7.4), 2.83 (t, 2H, J=7.4), 2.52 (q, 2H, J=7.6), 1.21 (t,3H, J=7.6). MS: m/z 477 (M+1).

4-(2-{(5-Ethylpyrimidin-2-yl)[4-(trifluoromethoxy)benzyl]amino}ethyl)-2-propylphenol

Step 1.

Alkylation of4-(2-{(5-ethylpyrimidin-2-yl)[4-(trifluoromethoxy)benzyl]amino}ethyl)phenol(2.07 g; 4.80 mmol) with allyl bromide (0.45 ml; 5.28 mmol) as pergeneral procedure C (1.1 eq. Cs₂CO₃, MeCN, 85C, 14 hr) providedN-{2-[4-(allyloxy)phenyl]ethyl}-5-ethyl-N-[4-(trifluoromethoxy)benzyl]pyrmidin-2-amine(2.0 g; 91% yield).

Step 2.

A solution of the above intermediate (2.0g; 4.38mmol) in dichloromethane(0.4M) is treated under nitrogen, in an ice bath, with boron trichloride(1M solution in hexane; 5.5 ml). After 1 hr. an additional 0.6 eq ofboron trichloride was added. Stirred for 30 more minutes and quenched bydropwise addition of methanol (3 ml). Stirred 15 minutes and partitionedbetween ethyl acetate and saturated sodium bicarbonate solution. Theaqueous phase was washed with ethyl acetate. The organic phases werewashed with saturated brine, dried over sodium sulfate and concentrated.Purification by flash chromatography on silica gel using an ethylacetate-hexane gradient (2-30%) afforded2-allyl-4-(2-{(5-ethylpyrimidin-2-yl)[4-(trifluoromethoxy)benzyl]amino}ethyl)phenolin good yield.

Step 3.

A solution of the above intermediate in ethyl acetate (˜0.3M) ishydrogenated over 10% Pd on carbon (500 mg) under balloon pressure.After 2 hours, fresh Pd catalyst was added (400 mg) and stirred oneextra hour. The catalyst was filtered off and washed with ethyl acetate,chloroform and methanol. The filtrate was concentrated and purified byflash chromatography on silica gel using an ethyl acetate-hexanegradient (5-40%) to afford the title compound in 54% overall yield forthe last two steps (1.20 g).

¹H NMR (CDCl₃) δ 8.25 (s, 2H), 7.21 (d, 2H, J=8.1), 7.12 (d, 2H, J=8.1),7.11 (s, 1H), 6.94 (d, 1H, J=1.9), 6.83 (dd, 1H, J=8.0; 1.9), 6.63 (d,1H, J=8.0), 4.75 (s, 2H), 3.78 (t, 2H, J=7.6), 2.84 (t, 2H, J=7.6), 2.55(q, 2H, J=7.8), 2.49 (q, 2H, J=7.6), 1.60 (m, 2H), 1.22 (t, 3H, J=7.6),0.95 (t, 3H, J=7.4).

[4-(2-{(5-Ethylpyrimidin-2-yl)[4-(trifluoromethoxy)benzyl]amino}ethyl)-2-propylphenoxy]aceticAcid

Step 1.

Alkylation of the intermediate phenol4-(2-{(5-ethylpyrimidin-2-yl)[4-(trifluoromethoxy)benzyl]amino}ethyl)-2-propylphenol(550 mg; 1.2 mmol) with tert-butyl bromoacetate (0.25 ml; 1.68 mmol) asper general procedure C (1.4 eq Cs2CO3, MeCN, 85C) afforded theintermediate tert-butyl ester (550 mg; 80% yield).

Step 2.

Hydrolysis of the tert-butyl ester (550 mg) with TFA as per generalprocedure I provided after chromatography and crystallization from ethylether-hexane, the title compound as a white solid (456 mg; 90% yield).

¹H NMR (CDCl₃) δ 8.24 (s, 2H), 7.20 (d, 2H, J=8.4), 7.11 (d, 2H, J=8.4),6.94 (m, 2H), 6.60 (d, 2H, J=7.9), 4.76 (s, 2H), 4.58 (s, 2H), 3.73 (t,2H, J=7.4), 2.81 (t, 2H, J=7.4), 2.59 (t, 2H, J=7.6), 2.49 (q, 2H,J=7.6), 1.59 (m, 2H), 1.21 (t, 3H, J=7.6), 0.93(t, 3H, J=7.4). MS: m/z518 (M+1).

5-Ethyl-N-{2-[3-propyl-4-(2H-tetraazol-5-ylmethoxy)phenyl]ethyl}-N-[4-(trifluoromethoxy)benzyl]pyrimidin-2-amine

Step 1.

Alkylation of the intermediate phenol4-(2-{(5-ethylpyrimidin-2-yl)[4-(trifluoromethoxy)benzyl]amino}ethyl)-2-propylphenol(550 mg; 1.2 mmol) with chloroacetonitrile (0.15 ml; 2.40 mmol) as pergeneral procedure C (2 eq Cs2CO3, MeCN, 85C) afforded the intermediatenitrile (530 mg; 88% yield).

Step 2.

A solution of the above intermediate (530 mg) in toluene (0.12 M) wastreated under nitrogen with azidotrimethylsilane (0.28 ml; 2.09 mmol)and dibutyltin oxide (0.052mg; 0.21 mmol). Heated to 110C for 14 hr.Cooled down and partitioned between ethyl acetate and 0.1N HCl. Theorganic phase was washed with saturated brine, dried over sodium sulfateand concentrated. Purification by radial chromatography using amethanol-dichloromethane gradient (1-15%) followed by crystallizationfrom acetone/water afforded the title compound as a white solid in 75%yield (427 mg).

¹H NMR (CDCl₃) δ 8.20 (s, 2H), 7.19 (d, 2H, J=8.3), 7.10 (d, 2H, J=8.3),6.91 (m, 2H), 6.72 (d, 1 H, J=7.5), 5.39 (bs, 2H), 4.74 (s, 2H), 3.73(t, 2H, J=7.5), 2.81 (t, 2H, J=7.5), 2.48 (m, 4H), 1.51 (q, 2H, J=7.3),1.20 (t, 3H, J=7.7), 0.89 (t, 3H, J=7.3).

2-(4-Methoxyphenyl)-2-methylpropan-1-amine

Step 1.

A solution of lithium diisopropylamide (2M; 61.1 ml; 122.3 mmol;) inheptane/THF/ethylbenzene was cooled in an ice bath and treated dropwise,under nitrogen, with a solution of (4-methoxy-phenyl)acetonitrile (6.0g; 40.77 mmol) in 30 ml of THF. After stirring for 45 minutes at 0C,iodomethane (12.69 ml; 203.85 mmol) was added and the mixture stirred atrt for 12 hours. The reaction mixture was added to a saturated solutionof ammonium chloride (300 ml) and extracted twice with ethyl acetate(200 ml). The organic phase was washed once with saturated brine (100ml), dried over sodium sulfate and concentrated to dryness. Purificationby flash chromatography on silica gel using an ethyl acetate/hexanegradient (5-30%) afforded 2-(4-methoxyphenyl)-2-methylpropanenitrile(6.0 g; 84% yield).

¹H NMR (CDCl₃) δ 7.36 (d, 2H, J=8.8), 6.88 (d, 2H, J=8.8), 3.78 (s, 3H),1.67 (s, 6H).

Step 2.

A suspension of lithium aluminum hydride (1.63 g; 42.86 mmol) in 20 mlof THF was treated dropwise, under nitrogen, with the previousintermediate (5.0 g; 28.57 mmol) in 30 ml of THF (exothermic). Heated toreflux for 3 hours. Cooled to rt and added additional lithium aluminumhydride (1.01 g; 26.61 mmol). Heated again to reflux for another 7hours. Cooled to rt and worked up by careful dropwise addition of 2.65ml of water, 2.65 ml of 15% NaOH and 7.90 ml of water. Stirred for 20minutes, diluted with ethyl acetate, filtered off the solids and washedthem with ethyl acetate (200 ml) and chloroform (100 ml). Afterconcentrating to dryness, the title compound was obtained (5.1 g), whichwas used without further purification.

¹H NMR (CDCl₃) δ 7.23 (d, 2H, J=8.8), 6.84 (d, 2H, J=8.8), 3.78 (s, 3H),2.73 (s, 2H), 1.25 (s, 6H).

2-[4-(2-{(5-Ethylpyrimidin-2-yl)[4-(trifluoromethyl)benzyl]amino}-1,1-dimethylethyl)phenoxy]-2-methylpropanoicAcid

Step 1.

Reductive amination of 2-(4-methoxyphenyl)-2-methylpropan-1-amine (500mg; 2.79 mmol) with 4-(trifluoromethyl)benzaldehyde (0.38 ml; 2.79 mmol)as per general procedure A affordedN-[2-(4-methoxyphenyl)-2-methylpropyl]-N-[4-(trifluoromethyl)benzyl]amine(792 mg; 84% yield).

¹H NMR (CDCl₃) δ 7.53 (d, 2H, J=8.1), 7.32 (d, 2H, J=8.1), 7.26 (d, 2H,J=8.8), 6.88 (d, 2H, J=8.8), 3.79 (s, 3H), 3.75 (s, 2H), 2.67 (s, 2H),1.34 (s, 6H).

Step 2.

Demethylation of the above intermediate (792 mg; 2.35 mmol) with borontribromide (1 M in dichloromethane; 9.4 ml; 9.4 mmol), as per generalprocedure F, afforded4-(1,1-dimethyl-2-{[4-(trifluoromethyl)benzyl]amino}ethyl)phenol as awhite solid (597 mg; 78% yield).

¹H NMR (CDCl₃) δ 7.52 (d, 2H, J=8.1), 7.33 (d, 2H, J=8.1), 7.17 (d, 2H,J=8.7), 6.73 (d, 2H, J=8.7), 3.77 (s, 2H), 2.67 (s, 2H), 1.32 (s, 6H).

Step 3.

Alkylation of the above intermediate (500 mg; 0.1.54 mmol) withethyl-2-bromoisobutyrate (0.45 ml; 3.1 mmol) as per general procedure C(2 eq Cs2CO3, MeCN, 85C, 15 hr) afforded ethyl2-[4-(1,1-dimethyl-2-{[4-(trifluoromethyl)benzyl]amino}ethyl)phenoxy]-2-methylpropanoate(82 mg; 95% yield).

¹H NMR (CDCl₃) δ 7.51 (d, 2H, J=8.2), 7.30 (d, 2H, J=8.2), 7.18 (d, 2H,J=8.8), 6.78 (d, 2H, J=8.8), 4.22 (q, 2H, J=7.1), 3.72 (s, 2H), 2.63 (s,2H), 1.57 (s, 6H), 1.30 (s, 6H), 1.22 (t, 3H, J=7.1). MS: m/z 438 (M+1).

Step 4.

Condensation of the above intermediate (200 mg; 0.46 mmol) with2-chloro-5-ethyl-pyrimidine (0.060 ml; 0.49 mmol) as per generalprocedure E (1.15 eq DIEA, 220C, 50 hr) afforded ethyl2-[4-(2-{(5-ethylpyrimidin-2-yl)[4-(trifluoromethyl)benzyl]amino}-1,1-dimethylethyl)phenoxy]-2-methylpropanoate(90 mg; 36% yield).

¹H NMR (CDCl₃) δ 8.1 (s, 2H), 7.40 (d, 2H, J=8.1), 7.20 (d, 2H, J=8.7),6.93 (d, 2H, J=8.1), 6.78 (d, 2H, J=8.7), 4.29 (s, 2H), 4.23 (q, 2H,J=7.2), 3.81 (s, 2H), 2.43 (q, 2H, J=7.6), 1.57 (s, 6H), 1.33 (s, 6H),1.24 (t, 3H, J=7.2), 1.17 (t, 3H, J=7.6). MS: m/z 544 (M+1).

Step 5.

Hydrolysis of the above ester (90 mg) with NaOH as per general procedureH provided after chromatography the title compound as a glassy solid (45mg; 52% yield). MS: m/z 516 (M+1).

N-[2-(4-Methoxyphenyl)-2-methylpropyl]-N-[4-(trifluoromethoxy)benzyl]amine

Reductive amination of 2-(4-methoxyphenyl)-2-methylpropan-1-amine (3.6g; 20.11 mmol) with 4-(trifluoromethoxy)benzaldehyde (3.82 g; 20.11mmol) as per general procedure A provided the title compound (5.0 g; 70%yield).

¹H NMR (CDCl₃) δ 7.26 (d, 2H, J=8.7), 7.24 (d, 2H, J=8.3), 7.13 (d, 2H;J=8.3), 6.86 (d, 2H, J=8.7), 3.80 (s, 3H), 3.70 (s, 2H), 2.68 (s, 2H),1.34 (s, 6H).

2-[4-(1,1-Dimethyl-2-{pyrimidin-2-yl[4-(trifluoromethoxy)benzyl]amino}ethyl)phenoxy]-2-methylpropanoicAcid

Step 1.

CondensationN-[2-(4-methoxyphenyl)-2-methylpropyl]-N-[4-(trifluoromethoxy)benzyl]amine(250 mg; 0.71 mmol) with 2-chloro-pyrimidine (85 mg; 0.74 mmol) as pergeneral procedure E (2 eq DIEA, 210C, 14 hr) affordedN-[2-(4-methoxyphenyl)-2-methylpropyl]-N-[4-(trifluoromethoxy)benzyl]pyrimidin-2-amine(270 mg; 88% yield). MS: m/z 432 (M+1).

Step 2.

Demethylation of the previous intermediate (250 mg; 0.58 mmol) withboron tribromide (1 M in dichloromethane; 2.31 ml; 2.31 mmol) as pergeneral procedure F afforded the intermediate phenol (200 mg; 84%yield).

MS: m/z 418 (M+1).

Step 3.

Alkylation of the intermediate phenol (100 mg; 0.24 mmol) with2-trichloromethyl-2-propanol (64 mg; 0.36 mmol) as per general procedureD provided after chromatography and crystallization fromdichloromethane-hexane, the title compound as a white solid (85 mg; 23%yield).

¹H NMR (CDCl₃) δ 8.21 (d, 2H, J=4.8), 7.18 (d, 2H, J=8.7), 6.95 (d, 2H,J=8.4), 6.81 (m, 4H), 6.42 (t, 1H, J=4.8), 4.23 (s, 2H), 3.77 (s, 2H),1.53 (s, 6H), 1.29 (s, 6H).

4-(2-{(5-Ethylpyrimidin-2-yl)[4-(trifluoromethoxy)benzyl]amino}-1,1-dimethylethyl)phenol

Step 1.

Condensation ofN-[2-(4-methoxyphenyl)-2-methylpropyl]-N-[4-(trifluoromethoxy)benzyl]amine(3.5 g; 9.92 mmol) with 2-chloro-5-ethyl-pyrimidine (1.51 g; 10.60 mmol)as per general procedure E (1.1 eq DIEA, 220C, 15 hr) afforded theintermediate methyl aryl ether (3.1 g; 68% yield).

¹H NMR (CDCl₃) δ 8.16 (s, 2H), 7.48 (s, 1H, OH), 7.22 (d, 2H, J=8.6),7.0 (d, 2H, J=8.2), 6.89 (d, 2H, J=8.6), 6.75 (d, 2H, J=8.2), 4.25 (s,2H), 3.85 (s, 2H), 2.45 (q, 2H, J=7.6), 1.35 (s, 6H), 1.18 (t, 3H,J=7.6). MS: m/z 460 (M+1).

Step 2.

Demethylation of the previous intermediate (2.32 g; 5.05 mmol) withboron tribromide (1M in dichloromethane; 20.2 ml; 20.2 mmol) as pergeneral procedure F provided the title compound (1.56 g; 69% yield).

¹H NMR (CDCl₃) δ 8.3 (s, 1H), 8.19 (s, 2H), 7.24 (d, 2H, J=8.6), 7.02(d, 2H, J=8.3), 6.93 (d, 2H, J=8.6), 6.77 (d, 2H, J=8.3), 4.30 (s, 2H),3.89 (s, 2H), 2.45 (q, 2H, J=7.5), 1.38 (s, 6H), 1.20 (t, 3H, J=7.5).

2-[4-(2-{(5-ethylpyrimidin-2-yl)[4-(trifluoromethoxy)benzyl]amino}-1,1-dimethylethyl)phenoxy]-2-methylpropanoicAcid

Alkylation of4-(2-{(5-ethylpyrimidin-2-yl)[4-(trifluoromethoxy)benzyl]amino}-1,1-dimethylethyl)phenol(7 g; 15.73 mmol) with 2-trichloromethyl-2-propanol (4.19 g; 23.60 mmol)as per general procedure D provided after flash chromatography the titlecompound (7.9 g; 94% yield).

¹H NMR (CDCl₃) δ 8.14 (s, 2H), 7.20 (d, 2H, J=8.7), 6.97 (d, 2H, J=8.3),6.84 (d, 2H, J=8.7), 6.82 (d, 2H, J=8.3), 4.24 (s, 2H), 3.78 (s, 2H),2.42 (q, 2H, J=7.5), 1.56 (s, 6H), 1.31 (s, 6H), 1.16 (t, 3H, J=7.5).MS: m/z 531 (M+1).

[4-(2-{(5-ethylpyrimidin-2-yl)[4-(trifluoromethoxy)benzyl]amino}-1,1-dimethylethyl)phenoxy]aceticAcid

Step 1.

Alkylation4-(2-{(5-ethylpyrimidin-2-yl)[4-(trifluoromethoxy)benzyl]amino}-1,1-dimethylethyl)phenol(95 mg; 0.21 mmol) with tert-butyl bromoacetate (50 mg; 0.26 mmol) asper general procedure C (1.2 eq Cs2CO3, MeCN, 80C, 3 hr) afforded theintermediate tert-butyl ester (100 mg; 84% yield).

¹H NMR (CDCl₃) δ 8.11 (s, 2H), 7.25 (d, 2H, J=8.8), 6.99 (d, 2H, J=8.4),6.85 (d, 2H, J=8.4), 6.82 (d, 2H, J=8.8), 4.49 (s, 2H), 4.27 (s, 2H),3.81 (s, 2H), 2.43 (q, 2H, J=7.6), 1.47 (s, 9H), 1.33 (s, 6H), 1.17 (t,3H, J=7.6). MS: m/z 560 (M+1).

Step 2.

Hydrolysis of the tert-butyl ester (100 mg) with TFA as per generalprocedure I provided after chromatography and crystallization fromdichloromethane-hexane, the TFA salt of the title compound as a glassysolid (94 mg; 90% yield).

¹H NMR (CDCl₃) δ 8.23 (s, 2H), 7.26 (d, 2H, J=8.6), 7.02 (d, 2H, J=8.2,6.89 (d, 2H, J=8.6), 6.83 (d, 2H, J=8.2), 4.63 (s, 2H), 4.36 (s, 2H),3.86 (s, 2H), 2.47 (q, 2H, J=7.6), 1.37 (s, 6H), 1.19 (t, 3H, J=7.6).MS: m/z 504 (M+1).

5-ethyl-N-{2-methyl-2-[4-(2H-tetraazol-5-ylmethoxy)phenyl]propyl}-N-[4-(trifluoromethoxy)benzyl]pyrimidin-2-amine

Step 1.

Alkylation of4-(2-{(5-ethylpyrimidin-2-yl)[4-(trifluoromethoxy)benzyl]amino}-1,1-dimethylethyl)phenol(150 mg; 0.34 mmol) with chloroacetonitrile (0.043 ml; 0.67 mmol) as pergeneral procedure C (2 eq Cs2CO3, MeCN, 85C, 12 hr) afforded theintermediate nitrile (125 mg; 76% yield).

¹H NMR (CDCl₃) δ 8.13 (s, 2H), 7.34 (d, 2H, J=8.8), 7.02 (d, 2H, J=8.3),6.91 (d, 2H, J=8.3), 6.88 (d, 2H, J=8.8), 4.76 (s, 2H), 4.35 (s, 2H),3.86 (s, 2H), 2.46 (q, 2H, J=7.6), 1.37 (s, 6H), 1.19 (t, 3H, J=7.6).

Step 2.

A solution of the previous intermediate (125 mg) in toluene (0.05 M) wastreated under nitrogen with azidotrimethylsilane (0.068 ml; 0.52 mmol)and dibutyltin oxide (0.013 mg; 0.05 mmol). Heated to 115C for 14 hr.Cooled down and partitioned between ethyl acetate and 0.1N HCl. Theorganic phase was washed with saturated brine, dried over sodium sulfateand concentrated. Purification by radial chromatography using amethanol-dichloromethane gradient (1-15%), followed by lyophillizationfrom MeCN-water afforded the title compound as a white powder (124 mg;91% yield).

¹H NMR (CDCl₃) δ 8.15 (s, 2H), 7.23 (d, 2H, J=8.8), 6.96 (d, 2H, J=8.3),6.83 (d, 2H, J=8.3), 6.79 (d, 2H, J=8.8), 5.36 (s, 2H), 4.33 (s, 2H),3.84 (s, 2H), 2.44 (q, 2H, J=7.6), 1.33 (s, 6H), 1.16 (t, 3H, J=7.6).

2-Chloro-4-(2-{(5-ethylpyrimidin-2-yl)[4-(trifluoromethoxy)benzyl]amino}-1,1-dimethylethyl)phenol

To a solution4-(2-{(5-ethylpyrimidin-2-yl)[4-(trifluoromethoxy)benzyl]amino}-1,1-dimethylethyl)phenol(300 mg; 0.67 mmol) in ethyl ether (0.1 M) was added sulfuryl chloride(0.060 ml; 0.74 mmol). After 10 minutes an additional 0.3 eq of sulfurylchloride were added. Stirred 20 more minutes. Partitioned between ethylacetate and dilute sodium bicarbonate solution. Organic phase was washedwith saturated brine, dried over sodium sulfate and concentrated.Purification by radial chromatography on silica gel using adichloromethane-hexane gradient (30-90%) provided the title compound (80mg; 25% yield).

¹H NMR (CDCl₃) δ 8.14 (s, 2H), 7.28 (d, 1 H, J=2.2), 7.17 (dd, 2H,J=8.5; 2.2), 7.04 (d, 2H, J=8.3), 6.91 (m, 3H), 5.92 (s, 1H, OH), 4.41(s, 2H), 3.84 (s, 2H), 2.46 (q, 2H, J=7.6), 1.34 (s, 6H), 1.20 (t, 3H,J=7.6). MS: m/z 480 (M+1).

[2-Chloro-4-(2-{(5-ethylpyrimidin-2-yl)[4-(trifluoromethoxy)benzyl]amino}-1,1-dimethylethyl)phenoxy]aceticAcid

Step 1.

Alkylation of2-chloro-4-(2-{(5-ethylpyrimidin-2-yl)[4-(trifluoromethoxy)benzyl]amino}-1,1-dimethylethyl)phenol(80 mg; 0.16 mmol) with tert-butyl bromoacetate (39 mg; 0.20 mmol) asper general procedure C (1.2 eq Cs2CO3, MeCN, 60C, 1 hr) afforded theintermediate tert-butyl ester (90 mg; 91% yield).

MS: m/z 594 (M+1).

Step 2.

Hydrolysis of the tert-butyl ester (90 mg) with TFA as per generalprocedure I provided after chromatography and lyophillization fromMeCN-water, the title compound as a white powder (72 mg; 88% yield).

¹H NMR (CDCl₃) δ 9.1 (bs, 1H), 8.17 (s, 2H), 7.35 (d, 1H, J=2.2), 7.16(dd, 2H, J=8.7; 2.2), 7.03 (d, 2H, J=8.4), 6.89 (d, 2H, J=8.4), 6.78 (d,1H, J=8.7), 4.69 (s, 2H), 4.42 (s, 2H), 3.82 (s, 2H), 2.45 (q, 2H,J=7.6), 1.33 (s, 6H), 1.17 (t, 3H, J=7.6). MS: m/z 538 (M+1).

2-[2-Chloro-4-(2-{(5-ethylpyrimidin-2-yl)[4-(trifluoromethoxy)benzyl]amino}-1,1-dimethylethyl)phenoxy]-2-methylpropanoicAcid

Step 1.

Alkylation of the intermediate phenol2-chloro-4-(2-{(5-ethylpyrimidin-2-yl)[4-(trifluoromethoxy)benzyl]amino}-1,1-dimethylethyl)phenol(70 mg; 0.15 mmol) with ethyl-2-bromoisobutyrate (57 mg; 0.29 mmol) asper general procedure C (2 eq Cs2CO3, MeCN, 85C, 5 hr) provided theintermediate ethyl ester (82 mg; 95% yield).

Step 2.

Hydrolysis of the ethyl ester (82 mg) with NaOH as per general procedureH provided after chromatography and lyophillization from MeCN-water, thetitle compound as a white powder (37 mg; 47% yield).

¹H NMR (CDCl₃) δ 8.15 (s, 2H), 7.37 (d, 1H, J=2.4), 7.15 (dd, 2H, J=8.6;2.4), 7.02 (d, 2H, J=8.3), 6.97 (d, 1H, J=8.6), 6.89 (d, 2H, J=8.3),4.38 (s, 2H), 3.82 (s, 2H), 2.45 (q, 2H, J=7.6), 1.61 (s, 6H), 1.34 (s,6H), 1.19 (t, 3H, J=7.6).

4-(2-{(5-Ethylpyrimidin-2-yl)[4-(trifluoromethoxy)benzyl]amino}-1,1-dimethylethyl)-2-propylphenol

Step 1.

Alkylation of4-(2-{(5-ethylpyrimidin-2-yl)[4-(trifluoromethoxy)benzyl]amino}-1,1-dimethylethyl)phenol(5.7 g; 12.96 mmol) with allyl bromide (1.23 ml; 14.26 mmol) as pergeneral procedure C (1.1 eq. Cs2CO3, MeCN, 85C, 14 hr) provided theintermediate allyl ether (5.3 g; 85% yield).

¹H NMR (CDCl₃) δ 8.16 (s, 2H), 7.29 (d, 2H, J=8.8), 7.03 (d, 2H, J=8.4),6.91 (d, 2H, J=8.4), 6.88 (d, 2H, J=8.8), 6.09 (m, 1H), 5.44 (dd, 1H,J==17.2; 1.5), 5.30 (dd, 1H, J=10.4; 1.1), 4.55 (d, 2H, J=5.3), 4.35 (s,2H), 3.86 (s, 2H), 2.46 (q, 2H, J=7.6), 1.38 (s, 6H), 1.21 (t, 3H,J=7.6).

Step 2.

A solution of the above intermediate (5.34g; 11.01 mmol) indichloromethane (0.12M) is treated under nitrogen, in an ice bath, withboron trichloride (1 M solution in hexane; 12.7 ml; 12.7 mmol). After 45minutes an additional 0.5 eq of boron trichloride was added. Stirred for15 more minutes and quenched by dropwise addition of methanol (3 ml).Stirred 15 minutes and partitioned between ethyl acetate and sodiumbicarbonate solution. The aqueous phase was washed with ethyl acetate.The organic phases were washed with saturated brine, dried over sodiumsulfate and concentrated. Purification by flash chromatography on silicagel using an ethyl acetate-hexane gradient (2-30%) afforded2-allyl-4-(2-(5-ethylpyrimidin-2-yl)[4-(trifluoromethoxy)benzyl]amino-1,1-dimethylethyl)phenol,which crystallized upon standing (3.4g; 64% yield).

¹H NMR (CDCl₃) δ 8.15 (s, 2H), 7.10 (m, 2H), 7.01 (d, 2H, J=8.4), 6.89(d, 2H, J=8.4), 6.71 (d, 1H, J=8.8), 6.01 (bs, 1H, OH), 5.99 (m, 1H),5.12 (m, 2H), 4.30 (s, 2H), 3.84 (s, 2H), 3.38 (d, 2H, J=6.2), 2.46 (q,2H, J=7.6), 1.35 (s, 6H), 1.20 (t, 3H, J=7.6). MS: m/z 486 (M+1).

Step 3.

A solution of the previous intermediate (125 mg; 0.26 mmol) in ethylacetate (0.05M) is hydrogenated over 10% Pd on carbon (60 mg) underballoon pressure for 3 hours. The catalyst was filtered off and washedwith ethyl acetate, chloroform and methanol. The filtrate wasconcentrated and purified by flash chromatography on silica gel using anethyl acetate-hexane gradient (2-25%) to afford the title compound (80mg; 64% yield).

¹H NMR (CDCl₃) δ 8.15 (s, 2H), 7.09 (d, 1H, J=2.3), 7.03 (dd, 1H, J=8.2;2.3), 7.0 (d, 2H, J=8.5), 6.87 (d, 2H, =8.5), 6.67 (d, 1H, J=8.2), 5.73(s, 1H, OH), 4.28 (s, 2H), 3.84 (s, 2H), 2.55 (t, 2H, J=7.5), 2.45 (q,2H, J=7.3), 1.61 (m, 2H), 1.35 (s, 6H), 1.19 (t, 3H, J=7.5), 0.94 (t,3H, J=7.3). MS: m/z 488 (M+1).

2-[4-(2-{(5-Ethylpyrimidin-2-yl)[4-(trifluoromethoxy)benzyl]amino}-1,1-dimethylethyl)-2-propylphenoxy]-2-methylpropanoicAcid

Step 1.

Alkylation of4-(2-{(5-ethylpyrimidin-2-yl)[4-(trifluoromethoxy)benzyl]amino}-1,1-dimethylethyl)-2-propylphenol(36 mg; 0.075 mmol) with ethyl-2-bromoisobutyrate (22 mg; 0.11 mmol) asper general procedure C (1.5 eq Cs2CO3, MeCN, 85C, 15 hr) afforded theintermediate ethyl ester (40 mg; 88% yield). MS: m/z 602 (M+1).

Step 2.

Hydrolysis of the ethyl ester (40 mg) with NaOH as per general procedureH provided after chromatography and lyophillization from MeCN-water, thetitle compound as a white powder (30 mg; 78% yield).

¹H NMR (CDCl₃) ε8.15 (s, 2H), 7.12 (d, 1H, J=2.3), 7.04 (dd, 1H. J=8.6;2.3), 6.99 (d, 2H, J=8.3), 6.83 (d, 2H, =8.3), 6.71 (d, 1H, J=8.6), 4.27(s, 2H), 3.81 (s, 2H), 2.55 (t, 2H, J=7.5), 2.45 (q, 2H, J=7.7), 1.60(s, 6H), 1.56 (m, 2H), 1.34 (s, 6H), 1.19 (t, 3H, J=7.5), 0.93 (t, 3H,J=7.7).

[4-(2-{(5-Ethylpyrimidin-2-yl)[4-(trifluoromethoxy)benzyl]amino}-1,1-dimethylethyl)-2-propylphenoxy]aceticAcid

Step 1.

Alkylation of4-(2-{(5-ethylpyrimidin-2-yl)[4-(trifluoromethoxy)benzyl]amino}-1,1-dimethylethyl)-2-propylphenol(36 mg; 0.075 mmol) with tert-butyl bromoacetate (18 mg; 0.090 mmol) asper general procedure C (1.2 eq Cs2CO3, MeCN, 85C, 2 hr) afforded theintermediate ester (40 mg; 88% yield). MS: m/z 602 (M+1).

Step 2.

Hydrolysis of the tert-butyl ester (40 mg) with TFA as per generalprocedure I provided after chromatography and lyophillization fromMeCN-water, the title compound as a white powder (35 mg; 95% yield).

¹H NMR (CDCl₃) δ 8.16 (s, 2H), 7.13 (d, 1H, J=2.3), 7.10 (dd, 1 H,J=8.5; 2.3), 7.0 (d, 2H, J=8.4), 6.85 (d, 2H, J=8.4), 6.66 (d, 1H,J=8.5), 4.65 (s, 2H), 4.32 (s, 2H), 3.83 (s, 2H), 2.61 (t, 2H, J=7.5),2.45 (q, 2H, J=7.6), 1.58 (m, 2H), 1.35 (s, 6H), 1.19 (t, 3H, J=7.5),0.93 (t, 3H, J=7.6).

5-Ethyl-N-{2-methyl-2-[3-propyl-4-(2H-tetraazol-5-ylmethoxy)phenyl]propyl}-N-[4-(trifluoromethoxy)benzyl]pyrimidin-2-amine

Step 1.

Alkylation of4-(2-{(5-ethylpyrimidin-2-yl)[4-(trifluoromethoxy)benzyl]amino}-1,1-dimethylethyl)-2-propylphenol(210 mg; 0.43 mmol) with chloroacetonitrile (0.055 ml; 0.86 mmol) as pergeneral procedure C (2 eq Cs2CO3, MeCN, 85C, 5 hr) afforded theintermediate nitrile (160 mg; 70% yield).

Step 2.

A solution of the previous intermediate (160 mg) in toluene (0.12 M) wastreated under nitrogen with azidotrimethylsilane (0.081 ml; 0.61 mmol)and dibutyltin oxide (0.015 mg; 0.06 mmol). Heated to 110C for 14 hr.Cooled down and partitioned between ethyl acetate and 0.1N HCl. Theorganic phase was washed with saturated brine, dried over sodium sulfateand concentrated. Purification by radial chromatography using amethanol-dichloromethane gradient (1-15%) afforded the title compound asa glassy solid (100 mg; 57% yield).

¹H NMR (CDCl₃) δ 8.13 (s, 2H), 7.09 (m, 2H), 6.98 (d, 2H, J=8.4), 6.84(d, 2H, J=8.4), 6.78 (d, 1H, J=9.2), 5.36 (s, 2H), 4.34 (s, 2H), 3.85(s, 2H), 2.45 (m, 4H), 1.46 (m, 2H), 1.33 (s, 6H), 1.15 (t, 3H, J=7.6),0.81 (t, 3H, J=7.3). MS: m/z 570 (M+1).

4-(2-{(5-Ethylpyrimidin-2-yl)[4-(trifluoromethoxy)benzyl]amino}-1-methylethyl)phenol

Step 1.

To a 2M solution of LDA in heptane (commercial grade; 66.2 ml) at 0C,under nitrogen, it was added 4-methoxyphenyl acetic acid (5.5 g; 33.09mmol). After stirring at 0C for 40 minutes it was added iodomethane(13.18 ml; 211.78 mmol). Allowed to warm to rt and stirred additional 30minutes. The reaction mixture was then added to 200 ml of saturatedammonium chloride. Extracted 3×150 ml of ethyl ether. The aqueous phasewas acidified with 1N HCl and extracted 2×150ml with ethyl ether. Thelatter organic phases were dried over sodium sulfate and concentrated toafford 5.8 g of an oil which corresponded to a 2.5:1 mixture of2-(4-methoxyphenyl)-2-methylpropanoic acid (bis-methylation product) to2-(4-methoxyphenyl)propanoic acid (monomethylation product) which wasused in the next step without any further purification.

Step 2.

The previous crude mixture (1.5 g) was dissolved in dichloromethane(˜0.6 M) and treated under nitrogen with EDCl (1.36 g; 7.09 mmol). After10 minutes, 4-trifluoromethoxybenzylamine (1.08 ml; 7.09 mmol) was addedand stirred for 1 hr. The reaction mixture is partitioned between ethylacetate and 0.5N HCl. The organic phase was washed 1×0.5N HCl, 2×0.5NNaOH, 1× saturated brine, dried over sodium sulfate and concentrated.Purification by flash chromatography on silica gel using an ethylacetate-hexane gradient (5-60%) afforded2-(4-methoxyphenyl)-N-[4-(trifluoromethoxy)benzyl]propanamide (0.38 g).

Step 3.

To a solution of the previous amide (375 mg; 1.06 mmol) in THF (0.2M),under nitrogen, it was added LAH (1M solution in THF; 2.12 ml; 2.12mmol). After stirring at rt for 1 hr additional LAH was added (2 ml).Stirred at rt for 14 hr and then heated at 80C for 4 hr. Cooled down andadded additional LAH (3 ml). Heated at 80C for an extra 6 hr. Thereaction was cooled down and worked up using the Fieser procedure: added0.27 ml of water dropwise (exothermic), followed by 0.27 ml of 15% NaOHsolution and 0.81 ml of water. Stirred for 10 minutes, diluted withethyl acetate and stirred another 10 minutes. The mixture was filteredthrough a plug of celite and the solids washed with ethyl acetate. Thefiltrate was concentrated to affordN-[2-(4-methoxyphenyl)propyl]-N-[4-(trifluoromethoxy)benzyl]amine (310mg) which was used in the next step without further purification. MS:m/z 340 (M+1).

Step 4.

Condensation of the previous amine (310 mg; 0.91 mmol) with2-chloro-5-ethyl pyrimidine (0.136 ml; 1.11 mmol) as per generalprocedure E (1.1 eq DIEA, toluene, 210C, 48 hr) afforded5-ethyl-N-[2-(4-methoxyphenyl)propyl]-N-[4-(trifluoromethoxy)benzyl]pyrimidin-2-amine(310 mg; 65% yield). MS: m/z 446 (M+1).

Step 5.

Demethylation of the previous intermediate (310 mg; 0.69 mmol) withboron tribromide (1M in dichloromethane; 2.78 ml) as per generalprocedure F provided the title compound (213 mg; 71% yield).

¹H NMR (CDCl₃) δ 8.2 (s, 2H), 7.07 (s, 4H), 7.02 (d, 2H, J=8.4), 6.70(d, 2H, J=8.4), 4.92 (d, 1H, J=16.3), 3.95 (d, 1H, J=16.3), 3.93 (m,1H), 3.25 (m, 2H), 2.46 (q, 2H, J=7.5), 1.23 (m, 6H). MS: m/z 432 (M+1).

2-[4-(2-{(5-Ethylpyrimidin-2-yl)[4-(trifluoromethoxy)benzyl]amino}-1-methylethyl)phenoxy]-2-methylpropanoicAcid

Alkylation of4-(2-((5-ethylpyrimidin-2-yl)[4-(trifluoromethoxy)benzyl]amino}-1-methylethyl)phenol(106 mg; 0.25 mmol) with 2-trichloromethyl-2-propanol (66 mg; 0.37 mmol)as per general procedure D provided after chromatography the titlecompound as a glassy solid (90 mg; 75% yield).

¹H NMR (CDCl₃) δ 8.22 (s, 2H), 7.04 (m, 6H), 6.84 (d, 2H, J=8.6), 4.86(d, 1H, J=16.3), 4.02 (d, 1H, J=16.3), 3.88 (dd, 1H, J=13.7; 6.4), 3.34(dd, 1H, J=13.7; 8.5), 3.25 (m, 1H), 2.47 (q, 2H, J=7.7), 1.56 (s, 6H),1.22 (m, 6H). MS: m/z 518 (M+1).

[4-(2-{(5-Ethylpyrimidin-2-yl)[4-(trifluoromethoxy)benzyl]amino}-1-methylethyl)phenoxy]aceticAcid

Step 1.

Alkylation of4-(2-{(5-ethylpyrimidin-2-yl)[4-(trifluoromethoxy)benzyl]amino}-1-methylethyl)phenol(106 mg; 0.25 mmol) with tert-butyl bromoacetate (0.043 ml; 0.29 mmol)as per general procedure C (1.2 eq Cs2CO3, MeCN, 85C, 3 hr) afforded theintermediate ethyl ester (100 mg; 77% yield).

Step 2.

Hydrolysis of the tert-butyl ester (100 mg) with TFA as per generalprocedure I provided after flash chromatography the title compound as aglassy solid.

¹H NMR (CDCl₃) δ 9.0 (bs, 1H), 8.23 (s, 2H), 7.09 (d, 2H, J=8.4), 7.06(bs, 4H), 6.82 (d, 2H, J=8.4), 4.86 (d, 1H, J=16.5), 4.57 (s, 2H), 4.15(d, 1H, J=16.5), 3.85 (dd, 1H, J=14; 6.9), 3.40 (dd, 1H, J=14; 8.2),3.26 (m, 1H), 2.47 (q, 2H, J=7.5), 1.23 (m, 6H). MS: m/z 490 (M+1).

5-Ethyl-N-[2-(4-methoxy-3-methylphenyl)ethyl]pyrimidin-2-amine

Step 1.

A solution of 3-methyl-p-anisaldehyde (23.13 g, 154 mmol) andnitromethane (9.40 g, 154 mmol) in MeOH (260 ml) was cooled in an icebath and treated dropwise with NaOH (162 ml of 1N solution; 162 mmol).The reaction mixture was stirred at rt for 1 hr. Water (50 ml) was thenadded and the mixture poured into 1N HCl (300 ml). The precipitate wascollected and purified by flash chromatography on silica gel elutingwith dichloromethane to provide methyl2-methyl-4-[(E)-2-nitroethenyl]phenyl ether as a yellow solid (14.61 g;49% yield).

¹H NMR (acetone d-6) δ 7.98 (d, 1H, J=13.6), 7.82 (d, 1H, J=13.6), 7.62(bs, 2H), 7.02 (d, 1H, J=8.9), 3.8 (s, 3H), 2.28 (s, 3H).

Step 2.

A solution of methyl 2-methyl-4-[(E)-2-nitroethenyl]phenyl ether (7.899; 40.88 mmol) in dry THF (50 ml) was added to borane (245 ml of 1Msolution in THF; 245 mmol), under nitrogen, dropwise over 20 minutes.The reaction mixture was then heated to 90C. After 14 hr it was cooledto rt and ice-cold water (100 ml) was added dropwise over 30 minutes.The pH was adjusted to ˜2 with 1N HCl and heated to reflux for 5 hr.Upon cooling, the reaction mixture was extracted with ethyl ether (2×300ml) and the ether phases were discarded. The pH of the aqueous phase wasadjusted to 10 with 1N NaOH and extracted with ethyl ether (2×200 ml).The combined organic phases were dried over MgSO₄, filtered andconcentrated to provide 2-(4-methoxy-3-methylphenyl)ethanamine (5.46 g;81% yield), which was used without any further purification.

¹H NMR (CDCl₃) δ 6.95 (d, 1H, J=8.2), 6.94 (s, 1H), 6.72 (d, 1H, J=8.0),3.8 (s, 3H), 2.88 (t, 2H, 6.8), 2.62 (t, 2H, 6.9), 2.18 (s, 3h).

Step 3. Condensation of 2-(4-methoxy-3-methylphenyl)ethanamine (516 mg;3.12 mmol) with 2-chloro-5-ethyl pyrimidine (446 mg; 3.12 mmol) as pergeneral procedure E (1.5 eq DIEA, nBuOH, 130C, 20 hr) provided5-ethyl-N-[2-(4-methoxy-3-20 methylphenyl)ethyl]pyrimidin-2-amine (435mg; 51% yield).

¹H NMR (CDCl₃) δ 8.1 (s, 2H), 7.0 (m, 2H), 6.74 (d, 1H, J=9), 5.0 (bs,1H), 3.8 (s, 3H), 3.60 (q, 2H, J=6.5), 2.88 (t, 2H, J=6.9), 2.44 (q, 2H,J=7.6), 2.18 (s, 3h), 1.18 (t, 3H, J=7.6).

5-Ethyl-N-[2-(3-fluoro-4-methoxyphenyl)ethyl]pyrimidin-2-amine

Similarly prepared from 3-fluoro-4-methoxybenzaldehyde.

5-Ethyl-N-[2-(4-methoxy-2,5-dimethylphenyl)ethyl]pyrimidin-2-amine

Similarly prepared from 4-methoxy-2,5-dimethylbenzaldehyde.

5-Ethyl-N-[2-(4-methoxy-2,3-dimethylphenyl)ethyl]pyrimidin-2-amine

Similarly prepared from 4-methoxy-2,3-dimethylbenzaldehyde.

5-Ethyl-N-{2-[4-methoxy-3-(trifluoromethyl)phenyl]ethyl}pyrimidin-2-amine

Similarly prepared from 4-methoxy-3-(trifluoromethyl)benzaldehyde.

N-[2-(3-chloro-4-methoxyphenyl)ethyl]-5-ethylpyrimidin-2-amine

Similarly prepared from 3-chloro-4-methoxybenzaldehyde.

5-Ethyl-N-[2-(4-methoxy-1-naphthyl)ethyl]pyrimidin-2-amine

Similarly prepared from 4-methoxy-1-naphthaldehyde.

N-[2-(3-Bromo-4-methoxyphenyl)ethyl]-5-ethylpyrimidin-2-amine

A mixture of 2-(3-bromo-4-methoxyphenyl)ethanamine (1 g; 4.35 mmol),2-chloro-5-ethyl-pyrimidine (0.56 g; 3.92 mmol) and DIEA (0.84 g; 6.53mmol) in n-butanol was heated to reflux for 14 hr. Upon cooling, thereaction mixture was concentrated and partitioned between 1N HCl andether. The aqueous phase was basified with 6N NaOH and extracted withether. The combined organic phases were washed with a saturated solutionof NaHCO3, dried over MgSO₄, filtered and concentrated to provide acolorless solid, which was triturated with hexane, filtered and dried toprovide the title compound as a white crystalline solid (0.89 g; 67%yield).

N-[2-(3-Bromo-4-methoxyphenyl)ethyl]-5-isopropylpyrimidin-2-amine

Similarly prepared from 2-(3-bromo-4-methoxyphenyl)ethanamine and2-chloro-5-isopropyl-pyrimidine (see below).

Synthesis of 2-chloro-5-isopropylpyrimidine:

Step 1.

A mixture of 3-ethoxy-2-isopropylprop-2-enal (ref. Menicagli, R. et al.Tetrahedron 1987, 43, 171-177) (250 mg, 1.76 mmol) and urea (250 mg,4.16 mmol) in ethanol (2.5 ml) was treated with concentrated HCl (0.5ml) and heated to reflux for 1 hour. Upon cooling, the reaction mixturewas neutralized with 1N NaOH (0.6 ml) and extracted with chloroform. Theorganic layer was dried over MgSO₄ and concentrated to provide5-isopropylpyrimidin-2(1H)-one as an off-white solid (0.20 g; 82%yield).

¹H NMR (CDCl₃) δ 8.15 (s, 2H), 2.72 (sept, 1H, J=6.9), 1.14 (d, 6H,J=6.9).

Step 2.

A mixture of 5-isopropylpyrimidin-2(1H)-one (2.1 g, 15.2 mmol), POCl₃(15 ml), and N,N-dimethylaniline (5 drops) was heated at reflux under anitrogen atmosphere for 2 h. Upon cooling, the majority of the POCl₃ wasremoved under reduced pressure. The residue was poured into ice waterand extracted with chloroform (3×20 ml). The combined organic extractswere washed with brine, dried over MgSO₄ and concentrated to provide2-chloro-5-isopropylpyrimidine as a light brown oil, which was usedwithout further purification.

¹H NMR (CDCl₃) δ 8.53 (s, 2H), 2.99 (sept, 1H, J=6.9), 1.34 (d, 6H,J=6.9).

5-Ethyl-N-[3-(4-methoxyphenyl)propyl]pyrimidin-2-amine

Similarly prepared from 2-(3-bromo-4-methoxyphenyl)ethanamine and2-chloro-5-ethyl-pyrimidine.

4-(2-{(5-Ethylpyrimidin-2-yl)[4-(trfluoromethoxy)benzyl]amino}ethyl)-2-methylphenol

Step 1.

A solution of5-ethyl-N-[2-(4-methoxy-3-methylphenyl)ethyl]pyrimidin-2-amine (0.83 g;3.07 mmol) and 4-trifluoromethoxy benzyl bromide (1.18 g; 4.61 mmol) indry DMF (6 ml) was treated under nitrogen with NaH (95% dispersion inoil; 0.12 g; 4.61 mmol) and the mixture heated at 60C for 1 hr. Cooledto rt and quenched with a saturated solution of ammonium chloride.Diluted with water and extracted with ethyl acetate. The organic phasewas dried over MgSO₄, filtered and concentrated . Purification by flashchromatography on silica gel using dichloromethane-hexane mixture (4:1)afforded5-ethyl-N-[2-(4-methoxy-3-methylphenyl)ethyl]-N-[4-(trifluoromethoxy)benzyl]pyrimidin-2-amine(1.26 g; 82% yield).

¹H NMR (CDCl₃) δ 8.18 (s, 2H), 7.2 (d, 2H, J=8.4), 7.1 (d, 2H, J=8.4),6.96 (bs, 2H), 6.74 (m, 1H), 4.72 (s, 2H), 3.8 (s, 3H), 3.7 (t, 2H,J=7.6), 2.78 (t, 2H, J=7.6), 2.45 (q. 2H, J=7.6), 2.16 (s, 3H), 1.18 (t,3H, J=7.6).

Step 2.

A solution of5-ethyl-N-[2-(4-methoxy-3-methylphenyl)ethyl]-N-[4-(trifluoromethoxy)benzyl]pyrimidin-2-amine(1.12 g; 2.53 mmol) in dichloromethane (70 ml) was cooled in an ice bathand treated under nitrogen with boron tribromide (1M solution indichloromethane; 2.78 ml). Allowed to warm to rt and additional borontribromide (2.53 ml) was added. Stirred for 2 hr and concentrated.Azeotroped 3× with MeOH, redissolved in MeOH and treated with sodiummethoxide (0.14 g; 2.53 mmol). Stirred for 30 minutes and concentrated.The residue was partitioned between ethyl acetate and water. The organicphase was dried over MgSO₄, filtered and concentrated to afford4-(2-{(5-ethylpyrimidin-2-yl)[4-(trifluoromethoxy)benzyl]amino}ethyl)-2-methylphenolas a dark brown oil (0.98 g; 90% crude yield) which was used insubsequent steps without further purification.

4-(2-{(5-Ethylpyrimidin-2-yl)[4-(trifluoromethyl)benzyl]amino}ethyl)-2-methyl phenol

Similarly prepared from5-ethyl-N-[2-(4-methoxy-3-methylphenyl)ethyl]pyrimidin-2-amine and4-trifluoromethylbenzyl bromide.

4-{2-[(4-Ethylbenzyl)(5-ethylpyrimidin-2-yl)amino]ethyl}-2-methylphenol

Similarly prepared from5-ethyl-N-[2-(4-methoxy-3-methylphenyl)ethyl]pyrimidin-2-amine and4-ethyl-benzyl bromide.

4-(2-{(5-Ethylpyrimidin-2-yl)[4-(trifluoromethyl)benzyl]amino}ethyl)-2-fluorophenol

Similarly prepared from5-ethyl-N-[2-(3-fluoro-4-methoxyphenyl)ethyl]pyrimidin-2-amine and4-trifluoromethyl benzyl bromide.

2-Chloro-4-(2-{(5-ethylpyrimidin-2-yl)[4-(trifluoromethoxy)benzyl]amino}ethyl)phenol

Similarly prepared fromN-[2-(3-chloro-4-methoxyphenyl)ethyl]-5-ethylpyrimidin-2-amine and4-trifluoromethoxy benzyl bromide.

2-Chloro-4-(2-{(5-ethylpyrimidin-2-yl)[3-(trifluoromethoxy)benzyl]amino}ethyl)phenol

Similarly prepared fromN-[2-(3-chloro-4-methoxyphenyl)ethyl]-5-ethylpyrimidin-2-amine and h3-trifluoromethoxy benzyl bromide.

2-Bromo-4-(2-{(5-ethylpyrimidin-2-yl)[4-(trifluoromethoxy)benzyl]amino}ethyl)phenol

Similarly prepared fromN-[2-(3-bromo-4-methoxyphenyl)ethyl]-5-ethylpyrimidin-2-amine and4-trifluoromethoxy benzyl bromide.

2-Bromo-4-(2-{(5-ethylpyrimidin-2-yl)[4-(trifluoromethyl)benzyl]amino}ethyl)phenol

Similarly prepared fromN-[2-(3-bromo-4-methoxyphenyl)ethyl]-5-ethylpyrimidin-2-amine and4-trifluoromethyl benzyl bromide.

2-Bromo-4-{2-[(4-ethylbenzyl)(5-ethylpyrimidin-2-yl)amino]ethyl}phenol

Similarly prepared fromN-[2-(3-bromo-4-methoxyphenyl)ethyl]-5-ethylpyrimidin-2-amine and4-ethyl benzyl bromide.

4-(2-{(5-Ethylpyrimidin-2-yl)[4-(trifluoromethoxy)benzyl]amino}ethyl)-2-(trifluoromethyl)phenol

Similarly prepared from5-ethyl-N-(2-[4-methoxy-3-(trifluoromethyl)phenyl]ethyl}pyrimidin-2-amineand 4-trifluoromethoxy benzyl bromide.

4-(2-{(5-Ethylpyrimidin-2-yl)[3-(trifluoromethoxy)benzyl]amino}ethyl)-2-(trifluoromethyl)phenol

Similarly prepared from5-ethyl-N-{2-[4-methoxy-3-(trifluoromethyl)phenyl]ethyl}pyrimidin-2-amineand 3-trifluoromethoxy benzyl bromide.

4-(2{(5-Ethylpyrimidin-2-yl)[3-(trifluoromethoxy)benzyl]amino}ethyl)-2,5-dimethylphenol

Similarly prepared from5-ethyl-N-[2-(4-methoxy-2,5-dimethylphenyl)ethyl]pyrimidin-2-amine and3-trifluoromethoxy benzyl bromide.

4-(2-{(5-Ethylpyrimidin-2-yl)[4-(trifluoromethoxy)benzyl]amino}ethyl)-2,5-dimethylphenol

Similarly prepared from5-ethyl-N-[2-(4-methoxy-2,5-dimethylphenyl)ethyl]pyrimidin-2-amine and4-trifluoromethoxy benzyl bromide.

4-(2-{(5-Ethylpyrimidin-2-yl)[4-(trifluoromethoxy)benzyl]amino}ethyl)-2,3-dimethylphenol

Similarly prepared from5-ethyl-N-[2-(4-methoxy-2,3-dimethylphenyl)ethyl]pyrimidin-2-amine and4-trifluoromethoxy benzyl bromide.

4-(2-{(5-Ethylpyrimidin-2-yl)[3-(trifluoromethoxy)benzyl]amino}ethyl)-2,3-dimethylphenol

Similarly prepared from5-ethyl-N-[2-(4-methoxy-2,3-dimethylphenyl)ethyl]pyrimidin-2-amine and3-trifluoromethoxy benzyl bromide.

4-(2-{(5-ethylpyrimidin-2-yl)[3-(trifluoromethoxy)benzyl]amino}ethyl)-2,3-dimethylphenol

Similarly prepared from5-ethyl-N-[2-(4-methoxy-1-naphthyl)ethyl]pyrimidin-2-amine.

4-(3-{(5-Ethylpyrimidin-2-yl)[3-(trifluoromethoxy)benzyl]amino}propyl)phenol

Similarly prepared from5-ethyl-N-[3-(4-methoxyphenyl)propyl]pyrimidin-2-amine and3-trifluoromethoxy benzyl bromide.

2-[4-(2-{(5-Ethylpyrimidin-2-yl)[4-(trifluoromethoxy)benzyl]amino}ethyl)-2-methylphenoxy]-2-methylpropanoicAcid

Step 1.

Alkylation of4-(2-{(5-ethylpyrimidin-2-yl)[4-(trfluoromethoxy)benzyl]amino}ethyl)-2-methylphenol(208 mg; 0.48 mmol) with ethyl-2-bromoisobutyrate (141 mg; 0.72 mmol) asper general procedure C (1.5 eq Cs2CO3, DMF, 80C, 72 hr) afforded theintermediate ethyl ester (104 mg; 40% yield).

¹H NMR (CDCl₃) δ 8.18 (s, 2H), 7.17 (d, 2H, J=8.4), 7.08 (d, 2H, J=8.4),6.96 (bs, 1H), 6.83 (d, 1H, J=8.1), 6.56 (d, 1H, J=8.3), 4.70 (s, 2H),4.2 (q, 2H, J=7.2), 3.7 (t, 2H, J=7.6), 2.78 (t, 2H, J=7.6), 2.45 (q,2H, J=7.6), 2.16 (s, 3H), 1.52 (s, 6H), 1.24 (t, 3H, J=7.0), 1.18 (t,3H, J=7.6).

Step 2.

Hydrolysis of the ethyl ester (104 mg) with LiOH as per generalprocedure H provided after workup the title compound as a light yellowsolid (94 mg; 97% yield).

¹H NMR (CDCl₃) δ 8.18 (s, 2H), 7.17 (d, 2H, J=8.4), 7.08 (d, 2H, J=8.4),6.96 (bs, 1H), 6.87 (d, 1H, J=8.1), 6.70 (d, 1H, J=8.1), 4.88 (s, 2H),3.9 (bs, 2H) 2.80 (t, 2H, J=7.4), 2.49 (q, 2H, J=7.6), 2.16 (s, 3H),1.52 (s, 6H), 1.20 (t, 3H, J=7.8).

2-[4-(2-{(5-Ethylpyrimidin-2-yl)[4-(trifluoromethyl)benzyl]amino}ethyl)-2-methylphenoxy]-2-methylpropanoicAcid

Similarly prepared from4-(2-{(5-ethylpyrimidin-2-yl)[4-(trifluoromethyl)benzyl]amino}ethyl)-2-methylphenol.

¹H NMR (CDCl₃) δ 8.26 (s, 2H), 7.5 (d, 2H, J=8.5), 7.25 (d, 2H, J=8.3),6.97 (s, 1H), 6.96 (d, 1H, J=8.4), 6.70 (d, 1H, J=8.1), 4.72 (s, 2H),3.78 (t, 2H, J=7.4), 2.80 (t, 2H, J=7.4), 2.49 (q, 2H, J=7.6), 2.17 (s,3H), 1.55 (s, 6H), 1.20 (t, 3H, J=7.6).

2-(4-{2-[(4-Ethylbenzyl)(5-ethylpyrimidin-2-yl)amino]ethyl}-2-methylphenoxy)-2-methylpropanoicAcid

Similarly prepared from4-{2-[(4-ethylbenzyl)(5-ethylpyrimidin-2-yl)amino]ethyl}-2-methylphenol.

¹H NMR (CDCl₃) δ 8.19 (s, 2H), 7.07 (s, 4H), 6.94 (d, 1H, J=8.8), 6.96(s, 1H), 6.86 (d, 1H, J=8.3), 6.70 (d, 1H, J=8.2), 4.71 (s, 2H), 3.69(t, 2H, J=7.5) 2.76 (t, 2H, J=7.4), 2.57 (q, 2H, J=7.6), 2.45 (q, 2H,J=7.8), 2.17 (s, 3H) 1.52 (s, 6H), 1.18 (m, 6H).

2-[4-(2-{(5-Ethylpyrimidin-2-yl)[4-(trifluoromethyl)benzyl]amino}ethyl)-2-fluorophenoxy]-2-methylpropanoicAcid

Similarly prepared from4-(2-{(5-ethylpyrimidin-2-yl)[4-(trifluoromethyl)benzyl]amino}ethyl)-2-fluorophenol.

¹H NMR (CDCl₃) δ 8.18 (s, 2H), 7.49 (d, 2H, J=8.0), 7.25 (d, 2H, J=7.8),6.94 (d, 1H, J=8.8), 6.91 (s, 1H), 6.84 (d, 1H, J=8.1), 4.78 (s, 2H),3.73 (t, 2H, J=7.5), 2.83 (t, 2H, J=7.4), 2.45 (q, 2H, J=7.8), 1.52 (s,6H), 1.18 (t, 3H, J=7.7).

2-[2-Chloro-4-(2-{(5-ethylpyrimidin-2-yl)[4-(trifluoromethoxy)benzyl]amino}ethyl)phenoxy]-2-methylpropanoicAcid

Similarly prepared from2-chloro-4-(2-{(5-ethylpyrimidin-2-yl)[4-(trifluoromethoxy)benzyl]amino}ethyl)phenol.

¹H NMR (CDCl₃) δ 8.20 (s, 2H), 7.21 (d, 1H, J=1.7), 7.18 (d, 2H, J=8.6),7.09 (d, 2H, J=8.5), 6.96-6.92 (m, 2H), 4.74 (s, 2H), 3.71 (t, 2H,J=7.5), 2.80 (t, 2H, J=7.4), 2.46 (q, 2H, J=7.6), 1.56 (s, 6H), 1.19 (t,3H, J=7.6).

2-[2-Chloro-4-(2{(5-ethylpyrimidin-2-yl)[3-(trifluoromethoxy)benzyl]amino}ethyl)phenoxy]-2-methylpropanoicAcid

Similarly prepared from2-chloro-4-(2-{(5-ethylpyrimidin-2-yl)[3-(trifluoromethoxy)benzyl]amino}ethyl)phenol.

¹H NMR (CDCl₃) δ 8.19 (s, 2H), 7.38 (s, 1H), 7.18 (m, 2H), 7.11 (m, 3H),6.84 (d, 1 H J=8.6), 4.74 (s, 2H), 3.72 (t, 2H, J=7.1), 2.84 (t, 2H,J=7.4), 2.46 (q, 2H, J=7.6), 1.60 (s, 6H), 1.19 (t, 3H, J=7.6).

2-(2-Bromo-4-{2-[(4-ethylbenzyl)(5-ethylpyrimidin-2-yl)amino]ethyl}phenoxy)-2-methylpropanoicAcid

Similarly prepared from2-bromo-4-{(2-[(4-ethylbenzyl)(5-ethylpyrimidin-2-yl)amino]ethyl}phenol.

¹H NMR (CDCl₃) δ 8.20 (s, 2H), 7.35 (s, 1H), 7.06-7.14 (m, 4H), 6.99 (d,1H, J=8.2), 6.89 (d, 1 H, J=8.2), 4.55 (s, 2H), 3.70 (t, 2H, J=7.5),2.78 (t, 2H, J=7.6), 2.59 (q, 2H, J=7.5), 2.46 (q, 2H, J-7.7), 1.19 (t,3H, J=7.5), 1.18 (t, 3H, J=7.7). MS: m/z 526, 528 (M+1).

2-[4-(2-{(5-Ethylpyrimidin-2-yl)[4-(trifluoromethoxy)benzyl]amino}ethyl)-2-(trifluoromethyl)phenoxy]-2-methylpropanoicAcid

Similarly prepared from4-(2-{(5-ethylpyrimidin-2-yl)[4-(trifluoromethoxy)benzyl]amino}ethyl)-2-(trifluoromethyl)phenol.

¹H NMR (CDCl₃) δ 8.18 (s, 2H), 7.6-7.3 (m, 4H), 7.08 (d, 2H, J=8.4),6.85 (d, 1H, J=7.7), 4.73 (s, 2H), 3.72 (t, 2H, J=7.5), 2.83 (t, 2H,J=7.5), 2.46 (q, 2H, 7.6), 1.52 (bs, 6H), 1.19 (t, 3H, J=7.6).

2-[4-(2-{(5-Ethylpyrimidin-2-yl)[3-(trifluoromethoxy)benzyl]amino}ethyl)-2-(trifluoromethyl)phenoxy]-2-methylpropanoicAcid

Similarly prepared from4-(2-{(5-ethylpyrimidin-2-yl)[3-(trifluoromethoxy)benzyl]amino}ethyl)-2-(trifluoromethyl)phenol.

¹H NMR (CDCl₃) δ 8.19 (s, 2H), 7.38 (s, 1H), 7.27-7.20 (m, 2H),7.10-7.03 (m, 3H), 6.84 (d, 1H J=8.4), 4.77 (s, 2H), 3.73 (t, 2H,J=7.1), 2.84 (t, 2H, J=7.4), 2.46 (q, 2H, J=7.6), 1.60 (s, 6H), 1.19 (t,3H, J=7.6).

2-[4-(2-{(5-Ethylpyrimidin-2-yl)[3-(trifluoromethoxy)benzyl]amino}ethyl)-2,5-dimethylphenoxy]-2-methylpropanoicAcid

Similarly prepared from4-(2-{(5-ethylpyrimidin-2-yl)[3-(trifluoromethoxy)benzyl]amino}ethyl)-2,5-dimethylphenol.

¹H NMR (CDCl₃) δ 8.19 (s, 2H), 7.29-7.25 (m, 1H), 7.12-7.04 (m, 3H),6.88 (s, 1H), 6.61 (s, 1H), 4.77 (s, 2H), 3.64 (t, 2H, J=7.6), 2.77 (t,2H, J=7.6), 2.46 (q, 2H, J=7.6), 2.20 (s, 3H), 2.13 (s, 3H), 1.52 (s,6H), 1.19 (t, 3H, J=7.6).

2-[4-(2-{(5-Ethylpyrimidin-2-yl)[4-(trifluoromethoxy)benzyl]amino}ethyl)-2,5-dimethylphenoxy]-2-methylpropanoicAcid

Similarly prepared from4-(2-{(5-ethylpyrimidin-2-yl)[4-(trifluoromethoxy)benzyl]amino}ethyl)-2,5-dimethylphenol.

¹H NMR (Acetone-D₆) δ 8.2 (s, 2H), 7.4 (bs, 2H), 7.2 (bs, 2H), 6.9 (s,1H), 6.691 (s, 1H), 4.77 (s, 2H), 3.7 (bs, 2H), 2.8 (bs, 2H), 2.46 (bs,2H), 2.20 (s, 3H), 2.13 (s, 3H), 1.52 (s, 6H), 1.19 (bs, 3H).

2-[4-(2-{(5-Ethylpyrimidin-2-yl)[4-(trifluoromethoxy)benzyl]amino}ethyl)-2,3-dimethylphenoxy]-2-methylpropanoicAcid

Similarly prepared from4-(2-{(5-ethylpyrimidin-2-yl)[4-(trifluoromethoxy)benzyl]amino}ethyl)-2,3-dimethylphenol.

¹H NMR (CDCl₃) δ 8.19 (s, 2H), 7.18 (d, 2H, J=8.4), 7.08 (d, 2H, J=8.3),6.83 (d, 1H, J=8.1), 6.62 (d, 1H, J=8.2), 4.73 (s, 2H), 3.614 (t, 2H,J=7.4), 2.847 (t, 2H, J=7.6), 2.46 (q, 2H, J=7.6), 2.19 (s, 3H), 2.13(s, 3H), 1.52 (s, 6H), 1.19 (t, 3H, J=7.6)

2-[4-(2-{(5-Ethylpyrimidin-2-yl)[3-(trifluoromethoxy)benzyl]amino}ethyl)-2,3-dimethylphenoxy]-2-methylpropanoicAcid

Similarly prepared from4-(2-{(5-ethylpyrimidin-2-yl)[3-(trifluoromethoxy)benzyl]amino}ethyl)-2,3-dimethylphenol.

¹H NMR (CDCl₃) δ 8.19 (s, 2H), 7.25 (m, 1H), 7.09-7.02 (m, 3H), 6.83(bd, 1H), 6.62 (d, 1H, J=8.1), 4.79 (s, 2H), 3.614 (bt, 2H), 2.847 (bt,2H), 2.46 (q, 2H, J=7.6), 2.19 (s, 3H), 2.13 (s, 3H), 1.52 (s, 6H), 1.19(t, 3H, J=7.6).

2-[2-Bromo-4-(2-{(5-ethylpyrimidin-2-yl)[4-(trifluoromethoxy)benzyl]amino}ethyl)phenoxy]-2-methylpropanoicAcid.

Alkylation of2-bromo-4-(2-{(5-ethylpyrimidin-2-yl)[4-(trifluoromethyl)benzyl]amino}ethyl)phenolwith 2-trichloromethyl-2-propanol as per procedure D, followed by astandard aqueous workup, provided the title compound as a light red oil.

¹H NMR (CDCl₃) δ 8.23 (s, 2H), 7.36 (d, 1H, J=8.0), 7.18 (d, 2H, J=8.4),7.10 (d, 2H, J=8.2), 6.99 (dd, 1H, J=8.2, 1.5), 6.89 (d, 1H, J=8.3),4.75 (s, 2H), 3.72 (t, 2H, J=7.3), 2.79 (t, 2H, J=7.7), 2.48 (q, 2H,J=7.5), 1.58 (s, 6H), 1.20 (t, 3H, J=7.5). MS: m/z 582, 584 (M+1).

2-[4-(2-{(5-Ethylpyrimidin-2-yl)[4-(trifluoromethoxy)benzyl]amino}ethyl)-2-methylphenoxy]propanoicAcid

Step 1.

Alkylation of4-(2-{(5-ethylpyrimidin-2-yl)[4-(trifluoromethoxy)benzyl]amino}ethyl)-2-methylphenol(284 mg; 0.66 mmol) with methyl 2-chloropropionate (89 mg; 0.73 mmol) asper general procedure C (1.5 eq Cs2CO3, DMF, 80C, 2 hr) afforded theintermediate methyl ester (152 mg; 44% yield).

¹H NMR (CDCl₃) δ 8.18 (s, 2H), 7.18 (d, 2H, J=8.4), 7.08 (d, 2H, J=8.4),6.96 (bs, 1H), 6.88 (d, 1H, J=8.3), 6.56 (d, 1H, J=8.3), 4.72 (s, 2H),4.70 (q, 1H, J=6.8), 3.7 (m, 5H), 2.78 (t, 2H, J=7.6), 2.45 (q, 2H,J=7.6), 2.21 (s, 3H), 1.59 (d, 3H, J=6.8), 1.18 (t, 3H, J=7.6).

Step 2.

Hydrolysis of the methyl ester (152 mg) with LiOH as per generalprocedure H provided after workup the title compound (140 mg; 95%yield).

¹H NMR (CDCl₃) δ 8.21 (s, 2H), 7.18 (d, 2H, J=8.6), 7.08 (d, 2H,J=8.611, 6.96 (bs, 1 H), 6.88 (d, 1H, J=8.3), 6.62 (d, 1H, J=8.3), 4.69(m, 3H), 3.7 (t, 2H, J=7.6), 2.76 (t, 2H, J=7.6), 2.45 (q, 2H, J=7.6),2.21 (s, 3H), 1.59 (d, 3H, J=6.8), 1.18 (t, 3H, J=7.6).

2-[4-(2-{(5-Ethylpyrimidin-2-yl)[4-(trifluoromethyl)benzyl]amino}ethyl)-2-methylphenoxy]propanoicAcid

Similarly prepared from4-(2-{(5-ethylpyrimidin-2-yl)[4-(trifluoromethyl)benzyl]amino}ethyl)-2-methylphenol.

¹H NMR (CDCl₃) δ 8.21 (s, 2H), 7.49 (d, 2H, J=8.1), 7.25 (d, 2H, J=8.0),6.95 (s, 1H), 6.88 (d, 1H, J=8.3), 6.60 (d, 1H, J=7.8), 4.78 (s, 2H),4.70 (q, 1H, J=7.1), 3.69 (t, 2H, J=7.5), 2.77 (t, 2H, J=7.6), 2.45 (q,2H, J=7.6), 2.21 (s, 3H), 1.61 (d, 3H, J=7.8), 1.18 (t, 3H, J=7.6).

2-(4-{2-[(4-Ethylbenzyl)(5-ethylpyrimidin-2-yl)amino]ethyl}-2-methylphenoxy)propanoicAcid

Similarly prepared from4-{2-[(4-ethylbenzyl)(5-ethylpyrimidin-2-yl)amino]ethyl}-2-methylphenol.

¹H NMR (CDCl₃) δ 8.29 (s, 2H), 7.09 (s, 4H), 6.95 (s, 1H), 6.91 (bs,1H), 6.62 (d, 1H, J=8.5), 4.73 (m, 3H), 3.72 (t, 2H, J=6.5), 2.8 (t, 2H,J=7.1), 2.58 (q, 2H, J=7.6), 2.50 (q, 2H, J=7.3), 1.67 (d, 3H, J=6.6),1.20 (t, 3H, J=7.6), 1.17 (t, 3H, J=7.6).

2-[4-(2-{(5-Ethylpyrimidin-2-yl)[4-(trifluoromethyl)benzyl]amino}ethyl)-2-fluorophenoxy]propanoicAcid

Similarly prepared from4-(2-{(5-ethylpyrimidin-2-yl)[4-(trifluoromethyl)benzyl]amino}ethyl)-2-fluorophenol.

¹H NMR (Acetone D₆) δ 8.24 (s, 2H), 7.60 (d, 2H, J=8.1), 7.44 (d, 2H,J=8.1), 7.03 (d, 1H, J=11.8), 6.93 (m, 2H), 4.908 (s, 2H), 4.84 (q, 1H,J=6.81), 3.81 (t, 2H, J=7.5), 2.87 (t, 2H, J=7.7), 2.48 (q, 2H, J=7.6),1.57 (d, 3H, J=67.8), 1.17 (t, 3H, J=7.5).

2-[2-Chloro-4-(2-{(5-ethylpyrimidin-2-yl)[4-(trifluoromethoxy)benzyl]amino}ethyl)phenoxy]propanoicAcid

Similarly prepared from2-chloro-4-(2-{(5-ethylpyrimidin-2-yl)[4-(trifluoromethoxy)benzyl]amino}ethyl)phenol.

¹H NMR (CDCl₃) δ 8.23 (s, 2H), 7.18 (m, 3H), 7.09 (d, 2H, J=8.2), 6.93(d, 2H, J=6.8)), 6.75 (d, 1H, J=8.2), 4.74 (m, 3H), 3.67 (t, 2H, J=7.5),2.75 (t, 2H, J=7.4), 2.46 (q, 2H, J-7.6), 1.67 (d. 3H, J=6.7), 1.19 (t,3H, J=7.6).

2-[2-bromo-4-(2-{(5-ethylpyrimidin-2-yl)[4-(trifluoromethoxy)benzyl]amino}ethyl)phenoxy]propanoicAcid

Step 1.

Alkylation of2-bromo-4-(2-{(5-ethylpyrimidin-2-yl)[4-(trifluoromethyl)benzyl]amino}ethyl)phenol(500 mg; 1.0 mmol) with t-butyl 2-bromopropionate (230 mg; 1.1 mmol) asper general procedure C (2 eq. K2CO3, acetone, reflux, 14 hr) providedthe intermediate tert-butyl ester (520 mg; 83% yield).

Step 2.

Hydrolysis of the tert-butyl ester (260 mg) with TFA as per generalprocedure I provided the title compound.

¹H NMR (CDCl₃) δ 8.23 (s, 2H), 7.36 (d, 1H, J=1.9), 7.19 (d, 2H, J=8.6),7.10 (d, 2H, J=8.3), 7.00 (d, 1H, J=7.2), 6.73 (d, 1H, J=8.5), 4.77 (s,2H), 4.75 (q, 1H, J=7.1), 3.70 (t, 2H, J=7.6), 2.77 (t, 2H, J=7.4), 2.48(q, 2H, J=7.6), 1.67 (d, 3H, J=6.9), 1.20 (t, 3H, J=7.6).

2-(2-Bromo-4-{2-[(4-ethylbenzyl)(5-ethylpyrimidin-2-yl)amino]ethyl}phenoxy)propanoicAcid

Similarly prepared from2-bromo-4-(2-{(5-ethylpyrimidin-2-yl)[4-(trifluoromethyl)benzyl]amino}ethyl)phenol.

¹H NMR (CDCl₃) δ 8.32 (s, 2H), 7.26 (d, 1H, J=1.7), 7.12 (d, 2H, J=8.4),7.10 (d, 2H, J=8.4), 6.99 (dd, 1H, J=8.4, 1.7), 6.71 (d, 1H, J=8.4),4.65-4.85 (m, 3H), 3.67-3.83 (m, 2H), 2.73 (t, 2H, J=7.3), 2.58 (q, 2H,J=7.5), 2.51 (q, 2H, J=7.5), 1.64 (d, 3H, J=6.98), 1.21 (t, 3H, J=7.3),1.19 (t, 3H, J=7.3). MS: m/z 512, 514 (M+1).

2-[2-Bromo-4-(2-{(5-ethylpyrimidin-2-yl)[4-(trifluoromethyl)benzyl]amino}ethyl)phenoxy]propanoicAcid

Similarly prepared from2-bromo-4-(2-{(5-ethylpyrimidin-2-yl)[4-(trifluoromethyl)benzyl]amino}ethyl)phenol.

¹H NMR (CDCl₃) δ 8.24 (s, 2H), 7.50 (d, 2H, J=8.1), 7.36 (s, 1H), 7.25(d, 2H, J=8.1), 6.95 (d, 1H, J=8.1), 6.70 (d, 1H, J=8.3), 4.79 (s, 2H),4.71 (q, 1H, J=6.8), 3.69 (t, 2H, J=7.9), 2.76 (t, 2H, J=7.5), 2.48 (q,2H, J=7.5), 1.66 (d, 3H, J=6.8), 1.19 (t, 3H, J=7.5). MS: m/z 552, 554(M+1).

[4-(2-{(5-Ethylpyrimidin-2-yl)[4-(trifluoromethoxy)benzyl]amino}ethyl)-2-methylphenoxy]aceticAcid

Step 1.

Alkylation of4-(2-{(5-ethylpyrimidin-2-yl)[4-(trifluoromethoxy)benzyl]amino}ethyl)-2-methylphenol(376 mg; 0.87 mmol) with tert-butyl chloroacetate (197 mg; 1.31 mmol) asper general procedure C (1.5 eq Cs2CO3, DMF, 80C, 2 hr) afforded theintermediate tert-butyl ester (224 mg; 47% yield).

¹H NMR (CDCl₃) δ 8.18 (s, 2H), 7.18 (d, 2H, J=8.4), 7.08 (d, 2H, J=8.4),6.96 (bs, 1H), 6.88 (d, 1H, J=8.3), 6.56 (d, 1H, J=8.3), 4.8(s, 2H),4.48 (s, 2H), 3.7 (t, 2H, J=7.6), 2.78 (t, 2H, J=7.6), 2.45 (q, 2H,J=7.6), 2.23 (s, 3H), 1.48 (s, 9H), 1.18 (t, 3H, J=7.6).

Step 2.

Hydrolysis of the tert-butyl ester (224 mg) with TFA as per generalprocedure I provided after chromatography the title compound (83 mg; 41%yield).

¹H NMR (CDCl₃) δ 8.18 (s, 2H), 7.18 (d, 2H, J=8.4), 7.08 (d, 2H, J=8.4),6.96 (bs, 1H), 6.88 (d, 1H, J=8.3), 6.56 (d, 1H, J=8.3), 4.8 (s, 2H),4.48 (s, 2H), 3.7 (t, 2H, J=7.6), 2.78 (t, 2H, J=7.6), 2.45 (q, 2H,J=7.6), 2.23 (s, 3H), 1.18 (t, 3H, J=7.6).

[4-(2-{(5-Ethylpyrimidin-2-yl)[4-(trifluoromethyl)benzyl]amino}ethyl)-2-fluorophenoxy]aceticAcid

Similarly prepared from4-(2-{(5-ethylpyrimidin-2-yl)[4-(trifluoromethyl)benzyl]amino}ethyl)-2-fluorophenol.

¹H NMR (CDCl₃) δ 8.27 (s, 2H), 7.51 (d, 2H, J=8.3), 7.26 (d, 2H, J=6.1),6.90 (d, 1H, J=10.7), 6.85-6.75 (m, 2H), 4.80 (s, 2H), 4.65 (s, 2H),3.75 (t, 2H, J=7.5), 2.82 (t, 2H, J=7.6), 2.49 (q, 2H, J=7.6), 1.18 (t,3H, J=7.6).

[2-Chloro-4-(2-{(5-ethylpyrimidin-2-yl)[4-(trifluoromethoxy)benzyl]amino}ethyl)phenoxy]aceticAcid

Similarly prepared from2-chloro-4-(2-((5-ethylpyrimidin-2-yl)[4-(trifluoromethoxy)benzyl]amino}ethyl)phenol.

¹H NMR (CDCl₃) δ 8.27 (s, 2H), 7.18 (m, 3H), 7.09 (d, 2H, J=8.4), 6.97(d, 2H, J=6.5)), 6.71 (d, 1H, J=8.3), 4.76 (s, 2H), 4.65 (s, 2H), 3.71(t, 2H, J=7.3), 2.78 (t, 2H, J=7.5), 2.49 (q, 2H, J=7.6), 1.20 (t, 3H,J=7.6).

(4-{2-[(4-Ethylbenzyl)(5-ethylpyrimidin-2-yl)amino]ethyl}-2-methylphenoxy)aceticAcid

Similarly prepared from4-{2-[(4-ethylbenzyl)(5-ethylpyrimidin-2-yl)amino]ethyl}-2-methylphenol.

¹H NMR (CDCl₃) δ 8.20 (s, 2H), 7.26-6.95 (bs, 4H), 6.92 (bs, 2H), 6.50(bs, 1H), 4.79 (s, 2H), 3.7 (bs, 2H), 2.79-2.25 (bm, 6H), 2.1 (s, 3H),1.18 (bs, 6H).

[4-(2-{(5-Ethylpyrimidin-2-yl)[4-(trifluoromethyl)benzyl]amino}ethyl)-2-methylphenoxy]aceticAcid

Similarly prepared from4-(2-{(5-ethylpyrimidin-2-yl)[4-(trifluoromethyl)benzyl]amino}ethyl)-2-methylphenol.

¹H NMR (CDCl₃) δ 8.21 (s, 2H), 7.49 (d, 2H, J=7.9), 7.26 (d, 2H, J=8.1),6.96 (s, 1H), 6.92 (d, 1H, J=8.1), 6.60 (d, 1H, J=8.3), 4.79 (s, 2H),5.59 (s, 2H), 3.71 (t, 2H, J=7.5), 2.79 (t, 2H, J=7.5), 2.46 (q, 2H,J=7.6), 2.22 (s, 3H), 1.19 (t, 3H, J=7.6).

[2-Bromo-4-(2-{(5-ethylpyrimidin-2-yl)[4-(trifluoromethyl)benzyl]amino}ethyl)phenoxy]aceticAcid

Similarly prepared from2-bromo-4-(2-{(5-ethylpyrimidin-2-yl)[4-(trifluoromethyl)benzyl]amino}ethyl)phenol.

¹H NMR (CDCl₃) δ 8.23 (s, 2H), 7.58-7.64 (d, 2H, J=8.6), 7.30-7.43 (m,3H), 7.08 (d, 1H, J=7.4), 6.81 (dd, 1H, J=8.5, 3.45), 4.82 (s, 2H), 4.60(s, 2H), 3.65-3.75 (m, 2H), 2.50-2.60 (m, 2H), 2.35-2.45 (m, 2H),1.05-1.15 (m, 3H). MS: m/z 538, 540 (M+1).

[2-Bromo-4-(2-{(5-ethylpyrimidin-2-yl)[4-(trifluoromethoxy)benzyl]amino}ethyl)phenoxy]aceticAcid

Similarly prepared from2-bromo-4-(2-{(5-ethylpyrimidin-2-yl)[4-(trifluoromethyl)benzyl]amino}ethyl)phenol.

¹H NMR (CDCl₃) δ 8.26 (s, 2H), 7.34 (d, 1H, J=1.4), 7.19 (d, 2H, J=8.5),7.11 (d, 2H, J=8.3), 7.02 (d, 1H, J=8.3), 6.66 (d, 1H, J=8.3), 4.77 (s,2H), 4.63 (s, 2H), 3.71 (t, 2H, J=7.6), 2.77 (t, 2H, J=7.6), 2.49 (q,2H, J=7.6), 1.20 (q, 3H, J=7.6). MS: m/z 554, 556 (M+1).

(2-Bromo-4-{2-[(4-ethylbenzyl)(5-ethylpyrimidin-2-yl)amino]ethyl}phenoxy)aceticAcid

Similarly prepared from2-bromo-4-(2-{(5-ethylpyrimidin-2-yl)[4-(trifluoromethyl)benzyl]amino}ethyl)phenol.

¹H NMR (CDCl₃) δ 8.18 (s, 2H), 7.36 (d, 1H, J=1.9), 7.06-7.12 (m, 4H),7.01 (dd, 1H, J=8.5, 1.9), 6.66 (d, 1H, J=8.5), 4.73 (s, 2H), 4.52 (s,2H), 3.69 (t, 2H, J=7.7), 2.77 (t, 2H, J=7.6), 2.57 (q, 2H), 2.45 (q,2H), 1.19 (t, 3H, J=7.6), 1.18 (t, 3H, J=7.6). MS: m/z 498, 500 (M+1).

[4-(3-{(5-Ethylpyrimidin-2-yl)[3-(trifluoromethoxy)benzyl]amino}propyl)phenoxy]aceticAcid

Similarly prepared from4-(3-{(5-ethylpyrimidin-2-yl)[3-(trifluoromethoxy)benzyl]amino}propyl)phenol.

¹H NMR (CDCl₃) δ 8.24 (s, 2H), 7.27 (t, 1H, J=8), 7.1-7.02 (m, 4H), 6.77(d, 2H, 8.4), 4.83 (s, 2H), 4.60 (s, 2H), 3.60 (bs, 2H), 2.55 (bs, 2H),2.47 (q, 2H, J=7.4), 1.87 (bs, 2H), 1.18 (t, 3H, J=7.6).

2-[2-Bromo-4-(2-{(5-isopropylpyrimidin-2-yl)[4-(trifluoromethoxy)benzyl]amino}ethyl)phenoxy]-2-methylpropanoicAcid

Step 1.

A solution ofN-[2-(3-bromo-4-methoxyphenyl)ethyl]-5-isopropylpyrimidin-2-amine (157mg; 0.45 mmol) in dry THF was treated under nitrogen with KtBuO (75 mg;0.67 mmol). After stirring for 15 minutes, 4-trifluoromethoxybenzylbromide (171 mg; 0.67 mmol) was added and stirred for 30 minutes. Thereaction was quenched by addition of an aqueous solution of NaHSO4 andextracted with dichloromethane. The organic phase was washed with brine,dried over MgSO4, filtered and concentrated to affordN-[2-(3-bromo-4-methoxyphenyl)ethyl]-5-isopropyl-N-[4-(trifluoromethoxy)benzyl]pyrimidin-2-amineas an oil in moderate yield, which was used in the next step withoutfurther purification

Step 2.

Demethylation of the previous intermediate with boron tribromide as pergeneral procedure F, afforded after chromatography the intermediatephenol as an oil in moderate yield.

Step 3.

Alkylation of the above phenol with 2-trichloromethyl-2-propanol as pergeneral procedure D afforded after chromatography the title compound.

¹H NMR (CDCl₃) δ 8.31 (d, 2H), 7.43 (d, ₁H, J=1.5), 7.05-7.33 (m, 5H),6.97 (d, 1H, J=8.4), 4.82 (s, 2H), 3.83 (t, 2H, J=7.2), 2.78-2.96 (m,3H), 1.64 (s, 6H), 1.29 (d, 6H, J=5.1). MS: m/z 596, 598 (M+1).

2-[2-Bromo-4-(2-{(5-isopropylpyrimidin-2-yl)[3-(trifluoromethoxy)benzyl]amino}ethyl)phenoxy]-2-methylpropanoicAcid

Similarly prepared by alkylation with 3-trifluoromethoxybenzyl bromide.

¹H NMR (CDCl₃) δ 8.28 (s, 2H), 6.86-7.50 (m, 7H), 4.83 (s, 2H),3.70-3.88 (m, 2H), 2.75-2.97 (m, 3H), 1.64 (s, 6H), 1.29 (d, 6H, J=6.9).MS: m/z 596, 598 (M+1).

2-{2-Bromo-4-[2-((5-isopropylpyrimidin-2-yl){4-[(trifluoromethyl)thio]benzyl}amino)ethyl]phenoxy}-2-methylpropanoicAcid

Similarly prepared by alkylation with 4-trifluoromethylthiobenzylbromide.

¹H NMR (CDCl₃) δ 8.32 (s, 2H), 7.62 (d, 2H, J=8.0), 7.42 (d, 1 H,J=1.7), 7.28, (d, 2H, J=8.0), 7.10 (d, 1H, J=8.0), 6.96 (d, 1H, J=8.4),4.86 (s, 2H), 3.85 (t, 2H, J=6.9), 2.80-2.94 (m, 3H), 1.64 (s, 6H), 1.30(d, 6H, J=5.4). MS: m/z 612, 614 (M+1).

The following 6 compounds were prepared using procedures similar tothose described above.

2-methyl-2-{4-[2-([4-(trifluoromethyl)benzyl]{5-[3-(trifluoromethyl)phenyl]pyrimidin-2-yl}amino)ethyl]phenoxy}propanoicAcid

2-[4-(2-{(5-cyanopyrimidin-2-yl)[4-(trifluoromethyl)benzyl]amino}ethyl)phenoxy]-2-methylpropanoicAcid

2-{4-[2-((5-ethylpyrimidin-2-yl){4-[(trifluoromethyl)sulfonyl]benzyl}amino)ethyl]phenoxy}-2-methylpropanoicAcid

2-{4-[2-((5-ethylpyrimidin-2-yl){4-[(trifluoromethyl)sulfinyl]benzyl}amino)ethyl]phenoxy}-2-methylpropanoicAcid

2-(4-{2-[(5-ethylpyrimidin-2-yl)(thien-2-ylmethyl)amino]ethyl}phenoxy)-2-methylpropanoicAcid

[4-(3-{(5-ethylpyrimidin-2-yl)[3-(trifluoromethoxy)benzyl]amino}propyl)phenoxy]aceticAcid

N-[2-(4-methoxyphenyl)ethyl]pyridin-2-amine

Step 1.

To a solution of 4-methoxyphenyl acetic acid (5 g; 30.08 mmol) in 30 mlof dichloromethane, under nitrogen, it was added1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (6.34 g; 33.09 mmol) insmall portions. After 10 minutes 2-aminopyridine (2.83 g; 30.08 mmol)was added and stirred for 4 hours at rt. The reaction mixture wasconcentrated and partitioned between ethyl acetate and 0.5N HCl. Theorganic phase was washed with 0.5N HCl (2×) and 0.5N NaOH (2×). The pHof the acidic/aqueous phase was adjusted to ˜7 with 0.5N NaOH andextracted twice with ethyl acetate. The basic/aqueous phase was alsoextracted twice with ethyl acetate. The combined organic phases werewashed with brine, dried over sodium sulfate and concentrated to afford2-(4-methoxyphenyl)-N-pyridin-2-ylacetamide (7 g; 92% yield), which wasused in the next step without further purification. MS: m/z 243 (M+1).

Step 2.

To a solution of the above intermediate (4.5 g; 18.60 mmol) in 40 ml ofdry THF, under nitrogen, it was added lithium aluminum hydride (1.7 g;44.74 mmol) slowly, in small portions (exothermic). After stirring at rtfor 4 hours, the reaction was worked up via the Fieser procedure: 1)added 1.7 ml of water, slowly, dropwise (exothermic); 2) added 1.7 ml of15% NaOH and 3) added 5.1 ml of water. After stirring for 10 minutes, itwas diluted with ethyl acetate and stirred an additional 30 minutes. Thesolids were filtered through a plug of celite and washed with ethylacetate. The filtrate was concentrated to dryness to afford the titlecompound (3.6 g; 84% crude yield) which was used without furtherpurification.

¹H NMR (CDCl₃) δ 8.02 (d, 1H, J=4.8), 7.35 (m, 1H), 7.09 (d, 2H, J=7.7),6.80 (d, 2H, J=7.7), 6.51 (m, 1H), 6.31 (d, 1H, J=8.3), 4.70 (bs, 1H),3.72 (s, 3H), 3.46 (broad q, 2H), 2.80 (broad t, 2H). MS: m/z 229 (M+1).

N-[2-(4-Methoxyphenyl)ethyl]-5-methylpyridin-2-amine

Similarly prepared from 4-methoxyphenyl acetic acid and2-amino-5-picoline.

MS: m/z 243 (M+1).

N-[2-(4-Methoxyphenyl)ethyl]-4-methylpyridin-2-amine

Similarly prepared from 4-methoxyphenyl acetic acid and2-amino-4-picoline.

MS: m/z 243 (M+1).

N-[2-(4-Methoxyphenyl)ethyl]-6-methylpyridin-2-amine

Similarly prepared from 4-methoxyphenyl acetic acid and2-amino-6-picoline.

MS: m/z 243 (M+1).

2-(4-{2-[[2,4-Bis(trifluoromethyl)benzyl](pyridin-2-yl)amino]ethyl}phenoxy)-2-methylpropanoicAcid

Step 1.

A solution of N-[2-(4-methoxyphenyl)ethyl]pyridin-2-amine (150 mg; 0.66mmol) in 3 ml of dioxane, under nitrogen, was treated with K₂CO3 (113mg; 0.82 mmol) and 2,4-bis-trifluoromethyl-benzyl bromide (0.13 ml; 0.69mmol) and heated in a pressure tube at 190-220C for 16 hours. Uponcooling, the reaction mixture was partitioned between ethyl acetate andsaturated sodium bicarbonate. The organic phase was washed withsaturated brine, dried over sodium sulfate and concentrated.Purification by radial chromatography on silica gel using an ethylacetate-hexane gradient (5-50%) affordedN-[2,4-bis(trifluoromethyl)benzyl]-N-[2-(4-methoxyphenyl)ethyl]pyridin-2-amine(130 mg; 44% yield).

¹H NMR (CDCl₃) δ 8.17 (d, 1H, J=3.8), 7.89 (s, 1H), 7.62 (d, 1H, J=8.2),7.46 (m, 1H), 7.37 (d, 1H, J=8.2), 7.09 (d, 2H, J=8.5), 6.81 (d, 2H,J=8.5), 6.61 (dd, 1H, J=7.1; 5.0), 6.47 (d, 1H, J=8.6), 4.89 (s, 2H),3.77 (s, 3H), 3.67 (t, 2H, J=7.7), 2.90 (t, 2H, J=7.7). MS: m/z 455(M+1).

Step 2.

The above intermediate (500 mg; 1.1 mmol) was mixed with pyridinehydrochloride (1500 mg) and set in an oil bath preheated to 220C. Themelted mixture was stirred at 220C for 1 hr. Upon cooling, the mixturewas partitioned between ethyl acetate and water. The organic phase waswashed with water and brine, dried over sodium sulfate and concentrated.Purification by radial chromatography on silica gel using an ethylacetate-hexane gradient (5-40%) afforded4-{2-[[2,4-bis(trifluoromethyl)benzyl](pyridin-2-yl)amino]ethyl}phenol(345 mg; 71% yield).

¹H NMR (CDCl₃) δ 8.17 (dd, 1H, J=5.1; 1.7), 7.86 (s, 1H), 7.60 (d, 1H,J=8.1), 7.50 (m, 1H), 7.36 (d, 1H, J=8.1), 6.98 (d, 2H, J=8.4), 6.68 (d,2H, J=8.4), 6.65 (dd, 1H, J=7.0; 5.1), 6.51 (d, 1H, J=8.6), 4.87 (s,2H), 3.68 (t, 2H, J=7.6), 2.88 (t, 2H, J=7.6). MS: m/z 441 (M+1).

Step 3.

A solution of the above phenol (150 mg; 0.34 mol) in 3 ml of acetone wastreated with 2-trichloromethyl-2-propanol (79 mg; 0.44 mmol) followed byslow addition of NaOH (triturated, 102 mg; 2.55 mmol) in small portions.After stirring at rt for 12 hr, the mixture was concentrated and theresidue partitioned between ethyl acetate and phosphate buffer (pH 7).The organic phase was washed with brine, dried over sodium sulfate andconcentrated. Purification by radial chromatography using amethanol-dichloromethane gradient (1-6%), followed by crystallizationfrom dichloromethane-hexane afforded the title compound as a white solid(103 mg; 57% yield).

¹H NMR (CDCl₃) δ 8.17 (dd, 1H, J=5.0; 1.6), 7.86 (s, 1H), 7.62 (d, 1H,J=8.1), 7.44 (m, 1H), 7.35 (d, 1H, J=8.1), 7.04 (d, 2H, J=8.5), 6.82 (d,2H, J=8.5), 6.61 (dd, 1H, J=7.0; 5.0), 6.41 (d, 1H, J=8.6), 4.80 (s,2H), 3.68 (t, 2H, J=7.4), 2.87 (t, 2H, J=7.4), 1.53 (s, 6H). MS: m/z 527(M+1).

2-Methyl-2-[4-(2-{pyridin-2-yl[4-(trifluoromethyl)benzyl]amino}ethyl)phenoxy]propanoicAcid

Similarly prepared from N-[2-(4-methoxyphenyl)ethyl]pyridin-2-amine and4-trifluoromethyl Benzyl Bromide.

¹H NMR (CDCl₃) δ 8.16 (d, 1H, J=3.8), 7.47 (d, 2H, J=8.1), 7.40 (m, 1H),7.20 (d, 2H, J=8.1), 7.01 (d, 2H, J=8.2), 6.81 (d, 2H, J=8.2), 6.58 (dd,1H, J=6.7; 5.3), 6.43 (d, 1H, J=8.6), 4.59 (s, 2H), 3.66 (t, 2H, J=7.4),2.81 (t, 2H, J=7.4), 1.53 (s, 6H). MS: m/z 459 (M+1).

2-(4-{2-[[2,4-Bis(trifluoromethyl)benzyl](4-methylpyridin-2-yl)amino]ethyl}phenoxy)-2-methylpropanoicAcid

Similarly prepared fromN-[2-(4-methoxyphenyl)ethyl]-4-methylpyridin-2-amine and2,4-bis-trifluoromethyl-benzyl Bromide.

¹H NMR (CDCl₃) δ 8.05 (d, 1H, J=5.2), 7.86 (s, 1H), 7.62 (d, 1H, J=8.0),7.35 (d, 1H, J=8.0), 7.0 (d, 2H, J=8.4), 6.80 (d, 2H, J=8.4), 6.47 (d,1H, J=5.2), 6.23 (s, 1H), 4.77 (s, 2H), 3.66 (t, 2H, J=7.3), 2.84 (t,2H, J=7.3), 2.22 (s, 3H), 1.52 (s, 6H). MS: m/z 541 (M+1).

2-(4-{2-[[2,4-Bis(trifluoromethyl)benzyl](5-methylpyridin-2-yl)amino]ethyl}phenoxy)-2-methylpropanoicAcid

Similarly prepared fromN-[2-(4-methoxyphenyl)ethyl]-5-methylpyridin-2-amine and2,4-bis-trifluoromethyl-benzyl Bromide.

¹H NMR (CDCl₃) δ 8.0 (d, 1H, J=2), 7.86 (s, 1H), 7.61 (d, 1H, J=8.2),7.35 (d, 1H, J=8.2), 7.27 (dd, 1H, J=8.6; 2.0), 7.02 (d, 2H, J=8.5),6.81 (d, 2H, J=8.5), 6.34 (d, 1H, J=8.6), 4.76 (s, 2H), 3.66 (t, 2H,J=7.4), 2.84 (t, 2H, J=7.4), 2.16 (s, 3H), 1.53 (s, 6H). MS: m/z 541(M+1).

2-(4-{2-[[2,4-Bis(trifluoromethyl)benzyl](6-methylpyridin-2-yl)amino]ethyl}phenoxy)-2-methylpropanoicAcid

Similarly prepared fromN-[2-(4-methoxyphenyl)ethyl]-6-methylpyridin-2-amine and2,4-bis-trifluoromethyl-benzyl Bromide.

¹H NMR (CDCl₃) δ 7.89 (s, 1H), 7.63 (d, 2H, J=8.1), 7.43 (d, 1H, J=8.1),7.34 (t, 1H, J=7.8), 7.08 (d, 2H, J=8.1), 6.85 (d, 2H, J=8.1), 6.46 (d,1H, J=7.8), 6.23 (d, 1H, J=7.8), 4.87 (s, 2H), 3.70 (t, 2H, J=7.2), 2.89(t, 2H, J=7.2), 2.37 (s, 3H), 1.57 (s, 6H).

2-Methyl-2-[4-(2-{(5-methylpyridin-2-yl)[4-(trifluoromethyl)benzyl]amino}ethyl)phenoxy]propanoicAcid

Similarly prepared fromN-[2-(4-methoxyphenyl)ethyl]-5-methylpyridin-2-amine and4-trifluoromethyl-benzyl bromide.

¹H NMR (CDCl₃) δ 8.0 (bs, 1H), 7.45 (d, 2H, J=8.1), 7.28 (dd, 1H, J=8.8;1.9), 7.18 (d, 2H, J=8.1), 6.96 (d, 2H, J=8.4), 6.80 (d, 2H, J=8.4),6.38 (d, 1H, J=8.8), 4.53 (s, 2H), 3.65 (t, 2H, J=7.3), 2.77 (t, 2H,J=7.3), 2.14 (s, 3H), 1.53 (s, 6H). MS: m/z 473 (M+1).

4-(2-{(5-Methylpyridin-2-yl)[3-(trifluoromethoxy)benzyl]amino}ethyl)phenol

Step 1.

Alkylation of N-[2-(4-methoxyphenyl)ethyl]-5-methylpyridin-2-amine with3-trifluoromethoxy-benzyl bromide as in the first step of the previousexamples affordedN-[2-(4-methoxyphenyl)ethyl]-5-methyl-N-[3-(trifluoromethoxy)benzyl]pyridin-2-amine.MS: m/z 417 (M+1).

Step 2.

Demethylation of the above intermediate with boron tribromide as pergeneral procedure F provided the title compound.

¹H NMR (CDCl₃) δ 8.5 (bs, 1H), 8.0 (d, 1H, J=2.0), 7.32 (dd, 1H, J=8.6;2.0), 7.23 (t, 1H, J=8.1), 7.0 (m, 3H), 6.98 (d, 2H, J=8.5), 6.73 (d,2H, J=8.5), 6.49 (d, 1H, J=8.6), 4.60 (s, 2H), 3.67 (t, 2H, J=7.5), 2.82(t, 2H, J=7.5), 2.17 (s, 3H).

2-Methyl-2-[4-(2-{(5-methylpyridin-2-yl)[3-(trifluoromethoxy)benzyl]amino}ethyl)phenoxy]propanoicAcid

Step 1.

Alkylation of4-(2-{(5-methylpyridin-2-yl)[3-(trifluoromethoxy)benzyl]amino}ethyl)phenolwith ethyl-2-bromo-isobutyrate (2 eq) as per general procedure C (2 eqCs2CO3, MeCN, 90C) afforded the intermediate ethyl ester.

MS: m/z 517 (M+1).

Step 2.

Hydrolysis of the intermediate ester with NaOH as per general procedureH afforded after chromatography the title compound as a glassy solid.

¹H NMR (CDCl₃) δ 11.9 (bs, 1H), 8.02 (d, 1H, J=2.0), 7.29 (dd, 1H,J=8.8; 2.0), 7.25 (t, 1H, J=7.9), 7.03 (broad d, 2H, J=7.9), 6.98 (broadd, 3H, J=8.4), 6.83 (d, 2H, J=8.4), 6.41 (d, 1H, J=8.8), 4.53 (s, 2H),3.67 (t, 2H, J=7.3), 2.78 (t, 2H, J=7.3), 2.16 (s, 3H), 1.55(s, 6H).

MS: m/z 489 (M+1).

[4-(2-{(5-Methylpyridin-2-yl)[3-(trifluoromethoxy)benzyl]amino}ethyl)phenoxy]aceticAcid

Similarly prepared by alkylation of4-(2-{(5-methylpyridin-2-yl)[3-(trifluoromethoxy)benzyl]amino}ethyl)phenolwith tert-butyl-bromo-acetate, followed by standard TFA hydrolysis(general procedure I).

¹H NMR (CDCl₃) δ 14.0 (bs, 1H), 8.0 (bs, 1H), 7.35 (dd, 1H, J=8.9; 2.0),7.27 (d, 1H, J=8.1), 7.03 (m, 5H), 6.77 (d, 2H, J=8.4), 6.45 (d, 1H,J=8.9), 4.56 (s, 2H), 4.49 (s, 2H), 3.71 (t, 2H, J=7.3), 2.80 (t, 2H,J=7.3), 2.16 (s, 3H). MS: m/z 461 (M+1).

4-(2-{(5-Methylpyridin-2-yl)[4-(trifluoromethyl)benzyl]amino}ethyl)-2-propylphenol

Step 1.

Alkylation of4-(2-{(5-methylpyridin-2-yl)[4-(trifluoromethyl)benzyl]amino}ethyl)phenol(110 mg; 0.30 mmol; an intermediate in the previously describedsynthesis of2-methyl-2-[4-(2-{(5-methylpyridin-2-yl)[4-(trifluoromethyl)benzyl]amino}ethyl)phenoxy]propanoicacid) with allyl bromide (0.027 ml; 0.31 mmol) as per general procedureC (1.1 eq Cs2CO₃, MeCN, 70 C) afforded the allyl ether intermediate (105mg; 86% yield).

Step 2.

A solution of the previous intermediate (105 mg; 0.25 mmol) in 5 ml ofdichloromethane was cooled in an ice bath, under nitrogen, and treatedwith boron trichloride (1M in hexane; 0.51 ml). After 20 minutes, thereaction was quenched by addition of 0.4 ml of methanol. After stirring5 minutes, the mixture was partitioned between ethyl acetate andsaturated K₂CO3. The organic phase was washed with brine, dried oversodium sulfate and concentrated. Purification by radial chromatographyusing an ethyl acetate-hexane gradient (5-30%) afforded2-allyl-4-(2-{(5-methylpyridin-2-yl)[4-(trifluoromethyl)benzyl]amino}ethyl)phenol.

Step 3.

A solution of the previous intermediate in ethyl acetate was treatedwith 10% Pd/C (0.5 weight equivalent) and hydrogenated under balloonpressure for 2 hr. The catalyst was filtered off and washed withchloroform, ethyl acetate and methanol. The filtrate was concentratedand purified by radial chromatography using an ethyl acetate-hexanegradient (5-30%) to afford the title compound (95 mg; 90% combined yieldfor the last two steps).

¹H NMR (CDCl₃) δ 8.0 (bs, 1H), 7.50 (d, 2H, J=8.1), 7.30 (dd, 1H, J=8.6;2.0), 7.27 (m, 2H), 6.88 (d, 1H, J=1.7), 6.83 (dd, 1H, J=8.1; 1.7), 6.66(d, 1H, J=8.1), 6.44 (d, 1H, J=8.6), 5.83 (bs, 1H, OH), 4.66 (s, 2H),3.65 (t, 2H, J=7.5), 2.81 (t, 2H, J=7.5), 2.52 (t, 2H, J=7.7), 2.18 (s,3H), 1.59 (m, 2H), 0.96 (t, 3H, J=7.3).

[4-(2-{(5-Methylpyridin-2-yl)[4-(trifluoromethyl)benzyl]amino}ethyl)-2-propylphenoxy]aceticAcid

Alkylation of4-(2-{(5-methylpyridin-2-yl)[4-(trifluoromethyl)benzyl]amino}ethyl)-2-propylphenolwith tert-butyl-bromo-acetate, followed by standard TFA hydrolysis (asdescribed in previous examples) provided after chromatography the titlecompound as a white foam.

¹H NMR (CDCl₃) δ 8.01 (bs, 1H), 7.50 (d, 2H, J=8.1), 7.31 (dd, 1H,J=8.8; 2.2), 7.24 (d, 2H, J=8.1), 6.89 (bs, 1H), 6.86 (dd, 1H, J=8.2;1.8), 6.60 (d, 1H, J=8.2), 6.41 (d, 1H, J=8.8), 4.59 (s, 2H), 4.53 (s,2H), 3.72 (t, 2H, J=7.5), 2.80 (t, 2H, J=7.5), 2.57 (t, 2H, J=7.7), 2.17(s, 3H), 1.57 (m, 2H), 0.90 (t, 3H, J=7.3).

5-Methyl-N-{2-[3-propyl-4-(2H-tetraazol-5-ylmethoxy)phenyl]ethyl}-N-[4-(trifluoromethyl)benzyl]pyridin-2-amine

The title compound was prepared from4-(2-{(5-methylpyridin-2-yl)[4-(trifluoromethyl)benzyl]amino}ethyl)-2-propylphenolvia a two-step sequence similar to that described for5-ethyl-N-{2-methyl-2-[3-propyl-4-(2H-tetraazol-5-ylmethoxy)phenyl]propyl}-N-[4-(trifluoromethoxy)benzyl]pyrimidin-2-amine.

¹H NMR (CDCl₃) δ 7.94 (s, 1H), 7.49 (d, 2H, J=8.2), 7.36 (dd, 1H, J=8.8;2.2), 7.21 (d, 2H, J=8.2), 6.75 (m, 3H), 6.48 (d, 1H, J=8.8), 5.34 (s,2H), 4.61 (s, 2H), 3.74 (t, 2H, J=7.2), 2.78 (t, 2H, J=7.2), 2.35 (t,2H, J=7.6), 2.17 (s, 3H), 1.38 (m, 2H), 0.75 (t, 3H, J=7.3).

2-Methyl-2-[4-(2-{[4-(trifluoromethyl)benzyl][5-(trifluoromethyl)pyridin-2-yl]amino}ethyl)phenoxy]propanoicAcid

A solution of ethyl2-methyl-2-[4-(2-{[4-(trifluoromethyl)benzyl]amino}ethyl)phenoxy]propanoate(250 mg; 0.61 mmol) in 3 ml of dioxane was treated with2-chloro-5-trifluoromethyl-pyridine (111 mg; 0.61 mmol) and K2CO3 (106mg; 0.76 mmol) and heated in a pressure tube at 220C overnight.Accidental loss of the solvent during heating produced a dark brownresidue, which was partitioned into ethyl acetate, water and methanol.The aqueous phase was washed with ethyl acetate. The combined organicphases were washed with brine, dried over sodium sulfate andconcentrated.

Under the reaction conditions described above, substantial ethyl esterhydrolysis occurred to produce the title compound directly, but itproved difficult to isolate from the crude mixture. For ease ofpurification, the crude acid was converted to the intermediate methylester using standard trimethylsilyldiazomethane/methanol conditions. Theester was subsequently purified by chromatography and hydrolyzed withNaOH using the standard protocol to provide the title compound (27 mg;9% yield).

¹H NMR (CDCl₃) δ 8.40 (s, 1H), 7.56 (d, 1H, J=9.0), 7.51 (d, 2H, J=7.9),7.22 (m, 2H), 7.06 (d, 2H, J=8.3), 6.85 (d, 2H, J=8.3), 6.42 (d, 1H,J=9.0), 4.67 (s, 2H), 3.73 (t, 2H, J=7.5), 2.87 (t, 2H, J=7.5), 1.55 (s,6H).

Ethyl2-[4-(2-{(5-bromopyridin-2-yl)[4-(trifluoromethyl)benzyl]amino}ethyl)phenoxy]-2-methylpropanoate

A solution of ethyl2-methyl-2-[4-(2-{[4-(trifluoromethyl)benzyl]amino}ethyl)phenoxy]propanoate(3 g; 7.3 mmol) in 7 ml of dioxane was treated under nitrogen with2,5-dibromopyridine (1.9 g; 8.1 mmol) and DIEA (1.4 ml; 8.1 mmol) andheated in a pressure tube for 2 days at 210C. Upon cooling, additionalDIEA (1.4 ml) was added and heated 2 more days. Upon cooling, thereaction mixture was partitioned between ethyl acetate and 0.5N HCl. Theorganic phase was washed with 0.5N HCl and saturated brine, dried oversodium sulfate and concentrated. Purification by silica gelchromatography using an ethyl acetate-hexane gradient (5-60%) affordedthe title compound (0.75 g; 18% yield).

¹H NMR (CDCl₃) δ 8.14 (d, 1H, J=2.6), 7.48 (d, 2H, J=8.1), 7.41 (dd, 1H,J=9.0; 2.6), 7.22 (d, 2H, J=8.1), 7.0 (d, 2H, J=8.5), 6.76 (d, 2H,J=8.5), 6.30 (d, 1H, J=9.0), 4.59 (s, 2H), 4.20 (q, 2H, J=7.1), 3.63 (t,2H, J=7.5), 2.81 (t, 2H, J=7.5), 1.54 (s, 6H), 1.20 (t, 3H, J=7.1).

2-[4-(2-{(5-bromopyridin-2-yl)[4-(trifluoromethyl)benzyl]amino}ethyl)phenoxy]-2-methylpropanoicAcid

Hydrolysis of ethyl2-[4-(2-{(5-bromopyridin-2-yl)[4-(trifluoromethyl)benzyl]amino}ethyl)phenoxy]-2-methylpropanoatewith NaOH as per general procedure H provided after chromatography andcrystallization from dichloromethane-hexane, the title compound as awhite solid (56 mg; 52% yield).

¹H NMR (CDCl₃) δ 8.16 (d, 1H, J=2.4), 7.50 (d, 2H, J=8.2), 7.44 (dd, 1H,J=9.0; 2.4), 7.21 (d, 2H, J=8.2), 7.03 (d, 2H, J=8.5), 6.84 (d, 2H,J=8.5), 6.31 (d, 1H, J=9.0), 4.58 (s, 2H), 3.66 (t, 2H, J=7.5), 2.83 (t,2H, J=7.5), 1.56 (s, 6H). MS: m/z 538 (M+1).

2-Methyl-2-[4-(2-{(5-phenylpyridin-2-yl)[4-(trifluoromethyl)benzyl]amino}ethyl)phenoxy]propanoicAcid

Step 1.

A solution of ethyl2-[4-(2-{(5-bromopyridin-2-yl)[4-(trifluoromethyl)benzyl]amino}ethyl)phenoxy]-2-methylpropanoate(150 mg; 0.27 mmol) in 2 ml of DMF is treated under nitrogen withtetrakis(triphenylphosphine)palladium (0) (31 mg; 0.027 mmol), phenylboronic acid (49 mg; 0.40 mmol) and sodium carbonate (0.27 ml of a 2Maqueous solution). The mixture was heated to 100C for 4 hours. Uponcooling, additional phenyl boronic acid (49 mg), Pd catalyst (31 mg) andNa2CO3 solution (0.27 ml) were added and heated again at 100C for 4 hr.Upon cooling, the mixture was partitioned between ethyl acetate andsaturated sodium carbonate. The organic phase was washed with saturatedsodium carbonate and brine, dried over sodium sulfate and concentrated.Purification by radial chromatography using an ethyl acetate-hexanegradient (5-50%) afforded the ethyl ester intermediate (67 mg; 45%yield). MS: m/z 563 (M+1).

Step 2.

Hydrolysis of the previous intermediate (67 mg) with NaOH as per generalprocedure H provided after chromatography and crystallization fromdichloromethane-hexane the title compound as a white solid (42 mg; 65%yield).

¹H NMR (CDCl₃) δ 8.45 (d, 1H, J=2.4), 7.68 (dd, 1H, J=8.8; 2.4), 7.50(t, 4H, J=7.3), 7.39 (t, 2H, J=7.6), 7.28 (m, 3H), 7.05 (d, 2H, J=8.4),6.85 (d, 2H, J=8.4), 6.52 (d, 1H, J=8.8), 4.64 (s, 2H), 3.72 (t, 2H,J=7.3), 2.87 (t, 2H, J=7.3), 1.55 (s, 6H). MS: m/z 535 (M+1).

2-[4-(2-{3,3′-Bipyridin-6-yl[4-(trifluoromethyl)benzyl]amino}ethyl)phenoxy]-2-methylpropanoicAcid

Similarly prepared using pyridine-3-boronic acid.

¹H NMR (CDCl₃) δ 8.81 (s, 1H), 8.50 (d, 1H, J=4.8), 8.39 (d, 1H, J=2.4),7.87 (d, 1H, J=8.0), 7.62 (dd, 1 H, J=9.0; 2.4), 7.48 (d, 2H, J=8.3),7.40 (dd, 1H, J=8.0; 4.8), 7.24 (d, 2H, J=8.3), 7.03 (d, 2H, J=8.5),6.88 (d, 2H, J=8.5), 6.49 (d, 1H, J=9.0), 4.65 (s, 2H), 3.71 (t, 2H,J=7.3), 2.85 (t, 2H, J=7.3), 1.59 (s, 6H). MS: m/z 536 (M+1).

2-[4-(2-{[5-(2-Furyl)pyridin-2-yl][4-(trifluoromethyl)benzyl]amino}ethyl)phenoxy]-2-methylpropanoicAcid

Similarly prepared using 2-furan-boronic acid.

¹H NMR (CDCl₃) δ 10.4 (bs, 1H), 8.50 (d, 1H, J=2.2), 7.68 (dd, 1H,J=9.0; 2.2), 7.49 (d, 2H, J=8.1), 7.39 (d, 1H, J=1.6), 7.23 (d, 2H,J=8.1), 7.05 (d, 2H, J=8.5), 6.84 (d, 2H, J=8.5), 6.41 (m, 3H), 4.64 (s,2H), 3.71 (t, 2H, J=7.4), 2.85 (t, 2H, J=7.4), 1.55 (s, 6H). MS: m/z 525(M+1).

2-Methyl-2-[4-(2-{(5-thien-2-ylpyridin-2-yl)[4-(trifluoromethyl)benzyl]amino}ethyl)phenoxy]propanoicAcid

Similarly prepared using 2-thiophene-boronic acid.

¹H NMR (CDCl₃) δ 8.45 (d, 1H, J=2.6), 7.62 (dd, 1H, J=8.8; 2.6), 7.50(d, 2H, J=8.3), 7.24 (d, 2H, J=8.3), 7.17 (d, 1H, J=5.0), 7.12 (d, 1H,J=3.5), 7.05 (d, 2H, J=8.5), 7.01 (dd, 1H, J=5.0; 3.5), 6.84 (d, 2H,J=8.5), 6.44 (d, 1H, J=8.8), 4.64 (s, 2H), 3.71 (t, 2H, J=7.4), 2.86 (t,2H, J=7.4), 1.55 (s, 6H). MS: m/z 541 (M+1).

2-[4-(2-{[5-(4-Methoxyphenyl)pyridin-2-yl][4-(trifluoromethyl)benzyl]amino}ethyl)phenoxy]-2-methylpropanoicAcid

Similarly prepared using 4-methoxyphenyl-boronic acid.

¹H NMR (CDCl₃) δ 8.39 (d, 1H, J=2.4), 7.62 (dd, 1H, J=8.8; 2.4), 7.50(d, 2H, J=8.1), 7.41 (d, 2H, J=8.8), 7.24 (d, 2H, J=8.1), 7.04 (d, 2H,J=8.5), 6.93 (d, 2H, J=8.8), 6.83 (d, 2H, J=8.5), 6.49 (d, 1H, J=8.8),4.62 (s, 2H), 3.80 (s, 3H), 3.72 (t, 2H, J=7.4), 2.85 (t, 2H, 7.4), 1.54(s, 6H).

2-[4-(2-{[5-(3-Methoxyphenyl)pyridin-2-yl][4-(trifluoromethyl)benzyl]amino}ethyl)phenoxy]-2-methylpropanoicAcid

Similarly prepared using 3-methoxyphenyl-boronic acid.

¹H NMR (CDCl₃) δ 8.44 (d, 1H, J=2.4), 7.66 (dd, 1H, J=8.8; 2.4), 7.50(d, 2H, J=8.3), 7.30 (t, 1H, J=7.9), 7.24 (d, 2H, J=8.3), 7.07 (m, 4H),6.83 (m, 3H), 6.50 (d, 1H, J=8.8), 4.64 (s, 2H), 3.82 (s, 3H), 3.73 (t,2H, J=7.4), 2.87 (t, 2H, 7.4), 1.55 (s, 6H).

2-[4-(2-{[5-(3-Furyl)pyridin-2-yl][4-(trifluoromethyl)benzyl]amino}ethyl)phenoxy]-2-methylpropanoicAcid

Similarly prepared using 3-furan-boronic acid.

¹H NMR (CDCl₃) δ 8.33 (d, 1H, J=2.3), 7.60 (s, 1H), 7.53 (dd, 1H, J=8.8;2.3), 7.50 (d, 2H, J=8.3), 7.42 (t, 1H, J=1.6), 7.24 (d, 2H, J=8.3),7.04 (d, 2H, J=8.5), 6.84 (d, 2H, J=8.5), 6.59 (bs, 1H), 6.46 (d, 1H,J=8.8), 4.62 (s, 2H), 3.72 (t, 2H, J=7.4), 2.85 (t, 2H, 7.4), 1.54 (s,6H).

2-[4-(2-{[5-(4-Acetylphenyl)pyridin-2-yl][4-(trifluoromethyl)benzyl]amino}ethyl)phenoxy]-2-methylpropanoicAcid

Similarly prepared using 4-acetyl-phenyl-boronic acid.

¹H NMR (CDCl₃) δ 8.5 (d, 1H, J=2.4), 7.97 (d, 2H, J=8.5), 7.71 (dd, 1H,J=9.0; 2.4), 7.57 (d, 2H, J=8.5), 7.50 (d, 2H, J=8.1), 7.24 (d, 2H,J=8.1), 7.06 (d, 2H, J=8.5), 6.85 (d, 2H, J=8.5), 6.53 (d, 1H, J=9.0),4.66 (s, 2H), 3.74 (t, 2H, J=7.4), 2.88 (t, 2H, 7.4), 2.59 (s, 3H), 1.54(s, 6H).

2-[4-(2-{3,4′-bipyridin-6-yl[4-(trifluoromethyl)benzyl]amino}ethyl)phenoxy]-2-methylpropanoicAcid

Similarly prepared using 4-pyridyl-boronic acid.

¹H NMR (CDCl₃) δ 8.6 (d, 2H, J=5.3), 8.54 (s, 1H), 7.72 (d, 1H, J=9.0),7.58 (d, 2H, J=5.3), 7.51 (d, 2H, J=8.1), 7.24 (d, 2H, J=8.1), 7.04 (d,2H, J=8.2), 6.87 (d, 2H, J=8.2), 6.51 (d, 1H, J=9.0), 4.68 (s, 2H), 3.73(t, 2H, J=7.4), 2.86 (t, 2H, 7.4), 1.58 (s, 6H).

MS: m/z 536 (M+1).

2-[4-(2-{[5-(3-Acetylphenyl)pyridin-2-yl][4-(trifluoromethyl)benzyl]amino}ethyl)phenoxy]-2-methylpropanoicAcid

Similarly prepared using 3-acetyl-phenyl-boronic acid.

¹H NMR (CDCl₃) δ 8.46 (s, 1H), 8.08 (s, 1H), 7.85 (d, 1H, J=7.7), 7.7(m, 2H), 7.50 (m, 3H), 7.26 (d, 2H, J=7.9), 7.07 (d, 2H, J=8.3), 6.85(d, 2H, J=8.3), 6.53 (d, 1H, J=9.0), 4.68 (s, 2H), 3.76 (t, 2H, J=7.4),2.89 (t, 2H, J=7.4), 2.62 (s, 3H), 1.55 (s, 6H).

MS: m/z 577 (M+1).

2-Methyl-2-[4-(2-{[5-(4-methylphenyl)pyridin-2-yl][4-(trifluoromethyl)benzyl]amino}ethyl)phenoxy]propanoicAcid

Similarly prepared using 4-methyl-phenyl-boronic acid.

¹H NMR (CDCl₃) δ 8.42 (d, 1H, J=2.2), 7.65 (dd, 1H, J=8.9; 2.2), 7.50(d, 2H, J=8.1), 7.38 (d, 2H, J=8.1), 7.25 (d, 2H, J=8.1), 7.20 (d, 2H,J=8.1), 7.06 (d, 2H, J=8.5), 6.84 (d, 2H, J=8.5), 6.51 (d, 1H, J=8.9),4.64 (s, 2H), 3.74 (t, 2H, J=7.4), 2.87 (t, 2H, 7.4), 2.35 (s, 3H), 1.55(s, 6H). MS: m/z 549 (M+1).

2-Methyl-2-{4-[2-([4-(trifluoromethyl)benzyl]{5-[2-(trifluoromethyl)phenyl]pyridin-2-yl}amino)ethyl]phenoxy}propanoicAcid

Similarly prepared using 2-trifluoromethyl-phenyl-boronic acid.

¹H NMR (CDCl₃) δ 8.15 (d, 1H, J=2.0), 7.73 (d, 1H, J=7.9), 7.52 (m, 3H),7.43 (m, 2H), 7.31 (m, 3H), 7.05 (d, 2H, J=8.4), 6.85 (d, 2H, J=8.4),6.48 (d, 1H, J=8.8), 4.69 (s, 2H), 3.72 (t, 2H, J=7.4), 2.88 (t, 2H,J=7.4), 1.55 (s, 6H). MS: m/z 603 (M+1).

2-[4-(2-{[5-(2-Chlorophenyl)pyridin-2-yl][4-(trifluoromethyl)benzyl]amino}ethyl)phenoxy]-2-methylpropanoicAcid

Similarly prepared using 2-chloro-phenyl-boronic acid.

¹H NMR (CDCl₃) δ 8.27 (d, 1H, J=2.4), 7.61 (dd, 1H, J=8.8; 2.4), 7.52(d, 2H; J=8.1), 7.43 (d, 1H, J=7.9), 7.29 (m, 5H), 7.06 (d, 2H, J=8.4),6.85 (d, 2H, J=8.4), 6.51 (d, 1H, J=8.8), 4.68 (s, 2H), 3.73 (t, 2H,J=7.3), 2.88 (t, 2H, J=7.3), 1.55 (s, 6H). MS: m/z 569 (M+1).

2-[4-(2-{[5-(2-Methoxyphenyl)pyridin-2-yl][4-(trifluoromethyl)benzyl]amino}ethyl)phenoxy]-2-methylpropanoicAcid

Similarly prepared using 2-methoxy-phenyl-boronic acid.

¹H NMR (CDCl₃) δ 8.38 (d, 1H, J=2.2), 7.70 (dd, 1H, J=8.8; 2.2), 7.50(d, 2H; J=8.2), 7.28 (m, 4H), 7.05 (d, 2H, J=8.4), 7.0 (t, 1H, J=7.5),6.95 (d, 1H, J=8.4), 6.84 (d, 2H, J=8.4), 6.5 (d, 1H, J=8.8), 4.65 (s,2H), 3.81 (s, 3H), 3.72 (t, 2H, J=7.4), 2.87 (t, 2H, J=7.4), 1.55 (s,6H). MS: m/z 565 (M+1).

2-Methyl-2-[4-(2-{(5-thien-3-ylpyridin-2-yl)[4-(trifluoromethyl)benzyl]amino}ethyl)phenoxy]propanoicAcid

Similarly prepared using 3-thiophene-boronic acid.

¹H NMR (CDCl₃) δ 8.46 (d, 1H, J=2.4), 7.65 (dd, 1H, J=8.8; 2.4), 7.50(d, 2H; J=8.1), 7.36 (m, 1H), 7.28 (m, 1H), 7.25 (d, 2H, J=8.1), 7.04(d, 2H, J=8.4), 6.85 (d, 2H, J=8.4), 6.48 (d, 1H, J=8.8), 4.64 (s, 2H),3.72 (t, 2H, J=7.4), 2.86 (t, 2H, J=7.4), 1.55 (s, 6H). MS: m/z 541(M+1).

2-Methyl-2-[4-(2-{[5-(3-methylphenyl)pyridin-2-yl][4-(trifluoromethyl)benzyl]amino}ethyl)phenoxy]propanoicAcid

Similarly prepared using 3-methyl-phenyl-boronic acid.

¹H NMR (CDCl₃) δ 8.43 (d, 1H, J=2.2), 7.66 (dd, 1H, J=8.8; 2.2), 7.50(d, 2H; J=8.1), 7.28 (m, 5H), 7.09 (m, 1H), 7.06 (d, 2H, J=8.4), 6.84(d, 2H, J=8.4), 6.50 (d, 1H, J=8.8), 4.65 (s, 2H), 3.73 (t, 2H, J=7.4),2.88 (t, 2H, J=7.4), 2.37 (s, 3H), 1.55 (s, 6H). MS: m/z 549 (M+1).

2-[4-(2-{[5-(4-Chlorophenyl)pyridin-2-yl][4-(trifluoromethyl)benzyl]amino}ethyl)phenoxy]-2-methylpropanoicAcid

Similarly prepared using 4-chloro-phenyl-boronic acid.

¹H NMR (CDCl₃) δ 8.41 (d, 1H, J=2.4), 7.62 (dd, 1H, J=9.0; 2.4), 7.50(d, 2H; J=8.3), 7.40 (d, 2H, J=8.6), 7.34 (d, 2H, J=8.6), 7.24 (d, 2H,J=8.3), 7.05 (d, 2H, J=8.4), 6.84 (d, 2H, J=8.4), 6.50 (d, 1H, J=9.0),4.64 (s, 2H), 3.73 (t, 2H, J=7.4), 2.86 (t, 2H, J=7.4), 1.55 (s, 6H).MS: m/z 569 (M+1).

2-[4-(2-{[5-(3-Chlorophenyl)pyridin-2-yl][4-(trifluoromethyl)benzyl]amino}ethyl)phenoxy]-2-methylpropanoicAcid

Similarly prepared using 3-chloro-phenyl-boronic acid.

¹H NMR (CDCl₃) δ 8.40 (d, 1H, J=2.4), 7.62 (dd, 1H, J=9.0; 2.4), 7.50(d, 2H; J=8.1), 7.45 (bs, 1H), 7.35 (d, 1H, J=7.8), 7.30 (t, 1H, J=7.8),7.24 (m, 3H), 7.06 (d, 2H, J=8.4), 6.85 (d, 2H, J=8.4), 6.50 (d, 1H,J=9.0), 4.65 (s, 2H), 3.73 (t, 2H, J=7.4), 2.87 (t, 2H, J=7.4), 1.55 (s,6H). MS: m/z 569 (M+1).

2-Methyl-2-[4-(2-{[5-(2-methylphenyl)pyridin-2-yl][4-(trifluoromethyl)benzyl]amino}ethyl)phenoxy]propanoicAcid

Similarly prepared using 2-methyl-phenyl-boronic acid.

¹H NMR (CDCl₃) δ 8.17 (d 1H, J=2.4), 7.51 (d, 2H, J=8.1), 7.45 (dd, 1H;J=8.8; 2.4), 7.27 (d, 2H, J=8.1), 7.22 (m, 4H), 7.05 (d, 2H, J=8.4),6.84 (d, 2H, J=8.4), 6.50 (d, 1H, J=8.8), 4.66 (s, 2H), 3.72 (t, 2H,J=7.4), 2.87 (t, 2H, J=7.4), 2.29 (s, 3H), 1.54 (s, 6H). MS: m/z 549(M+1).

2-Methyl-2-{4-[2-([4-(trifluoromethyl)benzyl]{5-[4-(trifluoromethyl)phenyl]pyridin-2-yl}amino)ethyl]phenoxy}propanoicAcid

Similarly prepared using 4-trifluoromethyl-phenyl-boronic acid.

¹H NMR (CDCl₃) δ 8.45 (d, 1H, J=2.4), 7.67 (dd, 1H; J=8.9; 2.4), 7.63(d, 2H, J=8.5), 7.58 (d, 2H, J=8.5), 7.51(d, 2H, J=8.2), 7.26 (d, 2H,J=8.2), 7.07 (d, 2H, J=8.6), 6.85 (d, 2H, J=8.6), 6.53 (d, 1H, J=8.9),4.68 (s, 2H), 3.75 (t, 2H, J=7.4), 2.89 (t, 2H, J=7.4), 1.55 (s, 6H).MS: m/z 603 (M+1).

2-Methyl-2-{4-[2-([4-(trifluoromethyl)benzyl]{5-[3-(trifluoromethyl)phenyl]pyridin-2-yl}amino)ethyl]phenoxy}propanoicAcid

Similarly prepared using 3-trifluoromethyl-phenyl-boronic acid.

¹H NMR (CDCl₃) δ 8.43 (d, 1H, J=2.4), 7.71 (s, 1H), 7.67 (m, 2H), 7.51(m, 4H), 7.25 (d, 2H, J=8.9), 7.07 (d, 2H, J=8.5), 6.85 (d, 2H, J=8.5),6.52 (d, 1H, J=9.0), 4.67 (s, 2H), 3.75 (t, 2H, J=7.4), 2.89 (t, 2H,J=7.4), 1.55 (s, 6H). MS: m/z 603 (M+1).

Ethyl2-[4-(2-{(5-bromopyridin-2-yl)[4-(trifluoromethoxy)benzyl]amino}ethyl)phenoxy]-2-methylpropanoate

Step 1.

A mixture of 2,5-dibromo-pyridine (5 g; 21.10 mmol) and tyramine (5.79g; 42.21 mmol) was heated at 200C for 1 hour. Upon cooling the residuewas taken up into ethyl acetate, water and 1N HCl. The phases wereseparated and the organic phase was washed twice with 1N HCl. Thecombined aqueous phases were basified to pH-9 with 2N NaOH and extractedtwice with ethyl acetate. The combined organic phases were washed withbrine, dried over sodium sulfate and concentrated to afford4-{2-[(5-bromopyridin-2-yl)amino]ethyl}phenol as a beige solid (5 g; 80%yield), which was used in the next step without further purification.

Step 2.

The previous intermediate (5 g; 17.06 mmol) was alkylated withethyl-2-bromo-isobutyrate (6.65 g; 34.12 mmol) as per general procedureC (2 eq Cs2CO3, MeCN, 80C, 15 hr). Purification by flash chromatography(5-20% ethyl acetate-hexane gradient) afforded ethyl2-(4-{2-[(5-bromopyridin-2-yl)amino]ethyl}phenoxy)-2-methylpropanoate(6.3 g; 91% yield).

Step 3.

A solution of the previous intermediate (1 g; 2.45 mmol) in 8 ml of dryDMF was treated under nitrogen with NaH (60% dispersion in oil; 123 mg;3.07 mmol). After stirring for 5 minutes, 4-trifluoromethoxy-benzylbromide (0.49 ml; 3.07 mmol) was added and the mixture heated at 90C for4 hours. Upon cooling the reaction mixture was partitioned between ethylacetate and 0.05N HCl. The organic phase was washed with 0.05N HCl andbrine, dried over sodium sulfate and concentrated. Purification by flashchromatography afforded the title compound (0.65 g; 45% yield).

¹H NMR (CDCl₃) δ 8.17 (d, 1H, J=2.4), 7.44 (dd, 1H, J=9.0; 2.1), 7.15(d, 2H, J=8.6), 7.10 (d, 2H, J=8.6), 7.01 (d, 2H, J=8.6), 6.77 (d, 2H,J=8.6), 6.31 (d, 2H, J=9.0), 4.55 (s, 2H), 4.22 (q, 2H, J=7.1), 3.64 (t,2H, J=7.4), 2.81 (t, 2H, J=7.4), 1.55 (s, 6H), 1.25 (t, 3H, J=7.1).

2-[4-(2-{(5-Ethylpyridin-2-yl)[4-(trifluoromethyl)benzyl]amino}ethyl)phenoxy]-2-methylpropanoicAcid

Step 1.

A solution of ethyl2-[4-(2-{(5-bromopyridin-2-yl)[4-(trifluoromethyl)benzyl]amino}ethyl)phenoxy]-2-methylpropanoate(150 mg; 0.27 mmol) in 2 ml of toluene was treated under nitrogen withtetrakis(triphenylphosphine)palladium (0) (61 mg; 0.053 mmol),vinyltributyltin (252 mg; 0.80 mmol), lithium chloride (34 mg; 0.80mmol) and 2,6-di-tert-butyl-4-methyl-phenol (3 mg). The mixture washeated at 110C overnight. Upon cooling, the mixture was diluted with 10ml each of ethyl acetate and water. A saturated solution of KF (10 ml)was added and the phases were separated. The organic phase was washedwith brine, dried over sodium sulfate and concentrated. Purification byradial chromatography using an ethyl acetate-hexane gradient (5-50%)afforded ethyl2-methyl-2-(4-{2-[[4-(trifluoromethyl)benzyl](5-vinylpyridin-2-yl)amino]ethyl}phenoxy)propanoate(71 mg; 52% yield).

MS: m/z 513 (M+1).

Step 2.

A solution of the previous intermediate (71 mg) in 3 ml of ethyl acetatewas treated with 10% Pd/C (25 mg) and hydrogenated under balloonpressure. After 3 hours additional catalyst (20 mg) was added andhydrogenated for another hour. The catalyst was filtered off and washedwith ethyl acetate and chloroform/methanol. The filtrate wasconcentrated and purified by radial chromatography to afford theintermediate ethyl ester (70 mg; 98% yield).

Step 3.

The previous intermediate (70 mg) was hydrolyzed with NaOH as pergeneral procedure H. Purification by radial chromatography (1-5%methanol-dichloromethane gradient) afforded the title compound as aglassy solid (22 mg; 35% yield).

¹H NMR (CDCl₃) δ 9.3 (bs, 1H), 8.01 (d, 1H, J=2.4), 7.46 (d, 2H, J=8.3),7.31 (dd, 1H, J=8.8; 2.4), 7.18 (d, 2H, J=8.3), 6.99 (d, 2H, J=8.5),6.81 (d, 2H, J=8.5), 6.40 (d, 1H, J=8.8), 4.54 (s, 2H), 3.65 (t, 2H,J=7.4), 2.78 (t, 2H, J=7.4), 2.48 (q, 2H, J=7.6), 1.54 (s, 6H), 1.15 (t,3H, J=7.6). MS: m/z 487 (M+1).

2-[4-(2-{(5-Ethylpyridin-2-yl)[4-(trifluoromethoxy)benzyl]amino}ethyl)phenoxy]-2-methylpropanoicAcid

Similarly prepared from ethyl2-[4-(2-{(5-bromopyridin-2-yl)[4-(trifluoromethoxy)benzyl]amino}ethyl)phenoxy]-2-methylpropanoateand vinyltributyltin. ¹H NMR (CDCl₃) δ 8.02 (d, 1H, J=2.0), 7.32 (dd,1H, J=8.8; 2.0), 7.12 (d, 2H, J=8.6), 7.07 (d, 2H, J=8.5), 7.0 (d, 2H,J=8.4), 6.82 (d, 2H, J=8.4), 6.42 (d, 1H, J=8.8), 4.50 (s, 2H), 3.67 (t,2H, J=7.4), 2.80 (t, 2H, J=7.4), 2.49 (q, 2H, J=7.6), 1.55 (s, 6H), 1.19(t, 3H, J=7.6). MS: m/z 503 (M+1).

2-Methyl-2-[4-(2-{(5-propylpyridin-2-yl)[4-(trifluoromethoxy)benzyl]amino}ethyl)phenoxy]propanoicAcid

Similarly prepared from ethyl2-[4-(2-{(5-bromopyridin-2-yl)[4-(trifluoromethoxy)benzyl]amino}ethyl)phenoxy]-2-methylpropanoateand allyltributyltin.

¹H NMR (CDCl₃) δ 8.0 (d, 1H, J=2.0), 7.33 (dd, 1H, J=9.0; 2.0), 7.08 (d,2H, J=8.6), 7.06 (d, 2H, J=8.6), 6.96 (d, 2H, J=8.5), 6.78 (d, 2H,J=8.5), 6.45 (d, 1H, J=9.0), 4.49 (s, 2H), 3.69 (t, 2H, J=7.4), 2.79 (t,2H, J=7.4), 2.41 (t, 2H, J=7.4), 1.54 (m, 2H), 1.50 (s, 6H), 0.90 (t,3H, J=7.4). MS: m/z 517 (M+1).

2-[4-(2-{[5-(3-Hydroxypropyl)pyridin-2-yl][4-(trifluoromethoxy)benzyl]amino}ethyl)phenoxy]-2-methylpropanoicAcid

Step 1.

A solution of ethyl2-[4-(2-{(5-bromopyridin-2-yl)[4-(trifluoromethoxy)benzyl]amino}ethyl)phenoxy]-2-methylpropanoate(500 mg; 0.86 mmol) in 3 ml of Et₃N was treated under nitrogen withtetrakis(triphenylphosphine)palladium (0) (99 mg; 0.086 mmol) and copper(I) iodide (16 mg; 0.086 mmol). After stirring at rt for 5 minutes,propargyl alcohol (72 mg; 1.29 mmol) was added and the mixture heated at65C for 7 hr. Upon cooling the reaction mixture was concentrated and theresidue was partitioned between ethyl acetate and 0.1N HCl. The organicphase was washed with 0.1N HCl and brine, dried over sodium sulfate andconcentrated. Purification by radial chromatography using ethylacetate-hexane mixtures (5-50% gradient) afforded ethyl2-[4-(2-{[5-(3-hydroxyprop-1-ynyl)pyridin-2-yl][4-(trifluoromethoxy)benzyl]amino}ethyl)phenoxy]-2-methylpropanoate.

Step 2.

A solution of the previous intermediate in ethyl acetate was treatedwith 10% Pd/C and hydrogenated under balloon pressure for 2 hr. Thecatalyst was filtered off and washed with ethyl acetate andchloroform/methanol. The filtrate was concentrated and purified byradial chromatography (5-40% ethyl acetate-hexane gradient) to affordethyl2-[4-(2-{[5-(3-hydroxypropyl)pyridin-2-yl][4-(trifluoromethoxy)benzyl]amino}ethyl)phenoxy]-2-methylpropanoate.

MS: m/z 561 (M+1). CD₃OD

Step 3.

The above ester was hydrolyzed with NaOH as per general procedure H.Purification by radial chromatography afforded the title compound as alight yellow foam (30 mg; 7% combined yield).

¹H NMR (CDCl₃+CD₃OD) δ 7.89 (d, 1H, J=2.0), 7.27 (dd, 1H, J=9.0; 2.0),7.12 (d, 2H, J=8.6), 7.06 (d, 2H, J=8.6), 7.0 (d, 2H, J=8.5), 6.77(d,2H, J=8.5), 6.38 (d, 1H, J=9.0), 4.52 (s, 2H), 3.63 (t, 2H, J=7.4), 3.55(t, 2H, J=6.4), 2.79 (t, 2H, J=7.4), 2.50 (t, 2H, J=7.5), 1.75 (m, 2H),1.50 (s, 6H). MS: m/z 533 (M+1).

Ethyl2-[4-(2-{(5-acetylpyridin-2-yl)[4-(trifluoromethyl)benzyl]amino}ethyl)phenoxy]-2-methylpropanoate

A mixture of ethyl2-methyl-2-[4-(2-{[4-(trifluoromethyl)benzyl]amino}ethyl)phenoxy]propanoate(1.05 g; 2.57 mmol), 2-chloro-5-acetyl-pyridine (0.4 0 g; 2.57 mmol) andDIEA (0.36 g; 2.83 mmol) was heated in a pressure tube at 180C for 5 hr.Upon cooling, the residue was chromatographed using 20% ethylacetate-hexane mixtures to afford ethyl2-[4-(2-{(5-acetylpyridin-2-yl)[4-(trifluoromethyl)benzyl]amino}ethyl)phenoxy]-2-methylpropanoate(0.48 g; 35% yield).

Ethyl2-[4-(2-{(5-acetylpyridin-2-yl)[4-(trifluoromethoxy)benzyl]amino}ethyl)phenoxy]-2-methylpropanoate

Similarly prepared from ethyl2-methyl-2-[4-(2-{[4-(trifluoromethoxy)benzyl]amino}ethyl)phenoxy]propanoateand 2-chloro-5-acetyl-pyridine.

2-[4-(2-{(5-Acetylpyridin-2-yl)[4-(trifluoromethyl)benzyl]amino}ethyl)phenoxy]-2-methylpropanoicAcid

Hydrolysis of ethyl2-[4-(2-{(5-acetylpyridin-2-yl)[4-(trifluoromethyl)benzyl]amino}ethyl)phenoxy]-2-methylpropanoatewith LiOH as per general procedure H afforded after a standard aqueousworkup the title compound.

¹H NMR (CD₃OD) δ 8.79 (d, 1H, J=2.2), 8.01 (dd, 1H, J=9.1 and 2.4), 7.62(d, 2H, J=8.1), 7.39 (d, 2H, J=8.0), 7.13 (d, 2H, J=8.4), 6.85 (d, 2H,J=8.5), 6.65 (d, 1H, J=9.3), 4.85 (s, 2H), 3.85 (t, 2H, J=7.1), 2.94 (t,2H, J=7.3), 2.56 (s, 3H), 1.49 (s, 6H). MS: m/z 501 (M+1).

2-[4-(2{(5-isopropylpyridin-2-yl)[4-(trifluoromethyl)benzyl]amino}ethyl)phenoxy]-2-methylpropanoicAcid

Step 1.

A solution of methyltriphenylphosphonium bromide (101 mg; 0.28 mmol) in0.76 ml of THF was treated under nitrogen with potassium tert-butoxide(0.28 ml of a 1M solution in tert-butanol). After 10 minutes, ethyl2-[4-(2-{(5-acetylpyridin-2-yl)[4-(trifluoromethyl)benzyl]amino}ethyl)phenoxy]-2-methylpropanoate(100 mg; 0.19 mmol) was added. After 2 hours the reaction mixture wasconcentrated and the residue was partitioned between ethyl acetate andwater. The organic phase was dried over sodium sulfate and concentrated.Purification by flash chromatography using 10% ethyl acetate-hexanemixtures afforded ethyl2-[4-(2-{(5-isopropenylpyridin-2-yl)[4-(trifluoromethyl)benzyl]amino}ethyl)phenoxy]-2-methylpropanoate(30 mg; 30% yield).

¹H NMR (CDCl₃) δ 8.30 (s, 1H), 7.57 (d, 1H, J=8.8), 7.51 (d, 2H, J=7.9),7.25 (d, 2H, J=7.7), 7.03 (d, 2H, J=8.0), 6.77 (d, 2H, J=8.3), 6.42 (d,1H, J=8.9), 5.23 (s, 1H), 4.92 (s, 1H), 4.66 (s, 2H), 4.21 (q, 2H,J=7.1), 3.69 (t, 2H, J=6.9), 2.85 (t, 2H, J=6.8), 2.09 (s, 3H), 1.55 (s,6H), 1.24 (t, 3H, J=7.2).

Step 2.

A solution of the previous intermediate in EtOH was treated with 10%Pd/C and hydrogenated under 1 atm of H2 for 4 hr. The catalyst wasfiltered off and washed with ethyl acetate. The filtrate wasconcentrated to afford ethyl2-[4-(2-{(5-isopropylpyridin-2-yl)[4-(trifluoromethyl)benzyl]amino}ethyl)phenoxy]-2-methylpropanoate.

¹H NMR (CD₃OD) δ 7.96 (s, 1H), 7.60 (d, 2H, J=8.1), 7.45 (d, 1H, J=8.8),7.36 (d, 2H, J=7.8), 7.13 (d, 2H, J=8.6), 6.80 (d, 2H, J=8.5), 6.58 (d,1H, J=8.9), 4.71 (s, 2H), 4.22 (q, 2H, J=7.1), 3.74 (t, 2H, J=7.4),2.92-2.84 (m, 3H), 1.56 (s, 6H), 1.36-1.21 (m, 9H).

Step 3.

Hydrolysis of the above ester with LiOH as per general procedure Hprovided after standard aqueous workup the title compound.

¹H NMR (CDCl₃) δ 8.04 (s, 1H), 7.48 (d, 2H, J=7.7), 7.36 (d, 1H, J=8.6)7.21 (d, 2H, J=7.7), 7.00 (d, 2H, J=8.0), 6.82 (d, 2H, J=8.1), 6.43 (d,1H, J=9.0), 4.56 (s, 2H), 3.67 (t, 2H, J=7.1), 2.83-2.76 (m, 3H), 1.54(s, 6H), 1.19 (d, 6H, J=6.8). MS: m/z 501 (M+1).

2-[4-(2-{5-Isopropylpyridin-2-yl)[4-(trifluoromethoxy)benzyl]amino}ethyl)phenoxy]-2-methylpropanoicAcid

Similarly prepared from ethyl2-[4-(2-{(5-acetylpyridin-2-yl)[4-(trifluoromethoxy)benzyl]amino}ethyl)phenoxy]-2-methylpropanoate.

¹H NMR (CD₃OD) δ 7.80 (d, 1H, J=1.6), 7.56 (dd, 1H, J=9.1 and 2.1), 7.24(d, 2H, J=8.4), 7.18 (d, 2H, J=8.4), 7.07 (d, 2H, J=8.2), 6.80 (d, 2H,J=8.4), 6.72 (d, 2H, J=9.2), 4.64 (s, 2H), 3.73 (t, 2H, J=7.4),3.28-2.79 (m, 3H), 1.50 (s, 6H), 1.19 (d, 6H, J=6.8).MS: m/z 517 (M+1).

2-[3-(2-{(5-Isopropylpyridin-2-yl)[4-(trifluoromethoxy)benzyl]amino}ethyl)phenoxy]-2-methylpropanoicAcid

Similarly prepared starting with 3-methoxyphenethylamine.

¹H NMR (CD₃OD) δ 7.87 (d, 1H, J=2.2), 7.43 (dd, 1H, J=8.8 and 2.4),7.23-7.07 (m, 5H), 6.81-6.70 (m, 3H), 6.57 (d, 1H, J=8.8), 4.60 (s, 2H),3.68 (t, 2H, J=7.3), 2.83-2.74 (m, 3H), 1.48 (s, 6H), 1.18 (d, 6H,J=6.9). MS: m/z 517 (M+1).

[3-(2-{(5-Isopropylpyridin-2-yl)[4-(trifluoromethoxy)benzyl]amino}ethyl)phenoxy]aceticAcid

Similarly prepared starting with 3-methoxyphenethylamine.

¹H NMR (CD₃OD) δ 7.92 (d, 1H, J=9.5), 7.62 (s, 1H), 7.31-7.09 (m, 7H),6.82 (d, 1H, J=4.5), 6.77 (d, 1H, J=8.4), 4.71 (s, 2H), 4.62 (s, 2H),3.91 (t, 2H, J=6.7), 2.98 (t, 2H, J=6.7), 2.90-2.89 (m, 1H), 1.21 (d,6H, J=6.8). MS: m/z 489 (M+1).

Ethyl2-[4-(2-{(5-formylpyridin-2-yl)[4-(trifluoromethoxy)benzyl]amino}ethyl)phenoxy]-2-methylpropanoate

A solution of ethyl2-methyl-2-[4-(2-{[4-(trifluoromethoxy)benzyl]amino}ethyl)phenoxy]propanoate(3.0 g; 7.05 mmol) in 8 ml of DMF was treated with6-chloronicotinaldehyde (0.91 g; 6.42 mmol) and K2CO3 (0.97 g; 7.05mmol). The reaction mixture was heated at 150C for 4 hr. Upon cooling,the mixture was partitioned between ethyl acetate and 0.05N HCl. Theorganic phase was washed with 0.05N HCl and brine, dried over sodiumsulfate, filtered and concentrated. Purification by flash chromatographyusing ethyl acetate-hexane mixtures (5-50%) afforded the title compound(2.3 g; 68% yield).

¹H NMR (CDCl₃) δ 9.77 (s, 1H), 8.57 (d, 1H, J=2.1), 7.87 (dd, 1H, J=9.0;2.1), 7.15 (d, 2H, J=8.8), 7.11 (d, 2H, J=8.8), 7.02 (d, 2H, J=8.5),6.76 (d, 2H, J=8.5), 6.49 (d, 1H, J=9.0), 4.67 (s, 2H), 4.21 (q, 2H,J=7.2), 3.72 (t, 2H, J=7.5), 2.85 (t, 2H, J=7.5), 1.54 (s, 6H), 1.23 (t,3H, J=7.2).

2-[4-(2-{(5-isobutylpyridin-2-yl)[4-(trifluoromethoxy)benzyl]amino}ethyl)phenoxy]-2-methylpropanoicAcid

Step 1.

A solution of isopropyltriphenylphosphonium bromide (326 mg; 0.75 mmol)in 1.5 ml of dry THF was treated in an ice bath, under nitrogen, withn-butyl lithium (0.425 ml of a 1.6M solution in hexane; 0.68 mmol),dropwise. After stirring for 15 minutes, this mixture was added, viasyringe, into an ice-cold solution of ethyl2-[4-(2-{(5-formylpyridin-2-yl)[4-(trifluoromethoxy)benzyl]amino}ethyl)phenoxy]-2-methylpropanoate(200 mg; 0.38 mmol) in 2 ml of dry THF. After stirring at rt overnight,the reaction mixture was partitioned between ethyl acetate and water.The organic phase was washed with water and brine, dried over sodiumsulfate, filtered and concentrated. Purification by radialchromatography using ethyl acetate-hexane mixtures (5-20% gradient)afforded ethyl2-methyl-2-[4-2-{[5-(2-methylprop-1-enyl)pyridin-2-yl][4-(trifluoromethoxy)benzyl]amino}ethyl)phenoxy]propanoate(70 mg; 33% yield).

Step 2.

A solution of the above intermediate (65 mg) in 3 ml of ethyl acetatewas treated with 10% Pd/C (60 mg) and hydrogenated under balloonpressure for 3 hr. The catalyst was filtered off and washed with ethylacetate and chloroform/methanol. The filtrate was concentrated andpurified by radial chromatography to afford ethyl2-[4-(2-{(5-isobutylpyridin-2-yl)[4-(trifluoromethoxy)benzyl]amino}ethyl)phenoxy]-2-methylpropanoate(44 mg; 68% yield). MS: m/z 559 (M+1).

Step 3.

The above ester (44mg) was hydrolyzed with NaOH as per general procedureH. Purification by radial chromatography afforded the title compound asa glassy solid (30 mg; 73% yield).

¹H NMR (CDCl₃) δ 7.81 (d, 1H, J=2.2), 7.24 (dd, 1H, J=8.8; 2.2), 7.14(d, 2H, J=8.5), 7.06 (d, 2H, J=8.5), 6.99 (d, 2H, J=8.3), 6.80 (d, 2H,J=8.3), 6.43 (d, 1H, J=8.8), 4.54 (s, 2H), 3.58 (t, 2H, J=7.4), 2.77 (t,2H, J=7.4), 2.27 (d, 2H, J=7.1), 1.71 (m, 1H), 1.45 (s, 6H), 0.84 (d,6H, J=6.7).

2-[4-(2-{(5-Butylpyridin-2-yl)[4-(trifluoromethoxy)benzyl]amino}ethyl)phenoxy]-2-methylpropanoicAcid

Similarly prepared using propyltriphenylphosphonium bromide/nbutyllitium.

¹H NMR (CDCl₃) δ 7.97 (d, 1H, J=2.2), 7.24 (dd, 1H, J=8.8; 2.2), 7.11(d, 2H, J=8.5), 7.05 (d, 2H, J=8.5), 6.95 (d, 2H, J=8.5), 6.72 (d, 2H,J=8.5), 6.37 (d, 1H, J=8.8), 4.53 (s, 2H), 3.60 (t, 2H, J=7.4), 2.77 (t,2H, J=7.4), 2.42 (d, 2H, J=7.6), 1.49 (m, 2H), 1.43 (s, 6H), 1.31 (m,2H), 0.89 (t, 3H, J=7.4).

2-[4-(2-{[5-(2-Cyanoethyl)pyridin-2-yl][4-(trifluoromethoxy)benzyl]amino}ethyl)phenoxy]-2-methylpropanoicAcid

Similarly prepared using diethyl (cyanomethyl) phosphonate/NaHMDS.

¹H NMR (CDCl₃) δ 8.4 (bs, 1H), 8.07 (d, 1H, J=2.2), 7.35 (dd, 1H, J=8.8;2.2), 7.14 (d, 2H, J=8.6), 7.09 (d, 2H, J=8.6), 7.02 (d, 2H, J=8.5),6.83 (d, 2H, J=8.5), 6.43 (d, 1H, J=8.8), 4.56 (s, 2H), 3.66 (t, 2H,J=7.4), 2.80 (m, 4H), 2.55 (t, 2H, J=7.2), 1.56 (s, 6H). MS: m/z 528(M+1)

2-Methyl-2-[4-(2-{[5-(2,2,2-trifluoroethyl)pyridin-2-yl][4-(trifluoromethoxy)benzyl]amino}ethyl)phenoxy]propanoicAcid

Step 1.

A solution of ethyl2-[4-(2-{(5-formylpyridin-2-yl)[4-(trifluoromethoxy)benzyl]amino}ethyl)phenoxy]-2-methylpropanoate(400 mg; 0.75 mmol) in 5 ml of dry THF was treated in an ice bath, undernitrogen, with trifluoromethyltrimethylsilane (128 mg; 0.90 mmol),followed by tetrabutylammonium fluoride (0.075 ml of a 1M solution inTHF; 0.075 mmol). The reaction mixture was allowed to warm to rt andstirred overnight. Additional trifluoromethyltrimethylsilane (128 mg;0.90 mmol) and tetrabutylammonium fluoride (0.075 ml) were added. After6 hours the previous reagents were added again in the same amounts.After stirring at rt overnight, the reaction mixture was partitionedbetween ethyl acetate and water. The organic phase was washed with waterand brine, dried over sodium sulfate and concentrated. Purification byradial chromatography using ethyl acetate-hexane mixtures (5-40%gradient) afforded ethyl2-methyl-2-[4-(2-{[5-(2,2,2-trifluoro-1-hydroxyethyl)pyridin-2-yl][4-(trifluoromethoxy)benzyl]amino}ethyl)phenoxy]propanoate(247 mg; 55% yield).

Step 2.

A solution of the above intermediate (210 mg; 0.35 mmol) in 6 ml ofdichloromethane was treated with phenyl chlorothionoformate (0.053 ml;0.39 mmol) and DMAP (94 mg; 0.77 mmol). After stirring at rt for 2 hr,the mixture was concentrated and the residue was partitioned betweenethyl acetate and 0.5N HCl. The organic phase was washed with 0.5N HCland brine, dried over sodium sulfate and concentrated. Purification byradial chromatography using a dichloromethane-hexane gradient (20-80%)followed by a methanol-dichloromethane gradient (1-3%) afforded ethyl2-methyl-2-(4-{2-[[4-(trifluoromethoxy)benzyl](5-{2,2,2-trifluoro-1-[(phenoxycarbonothioyl)oxy]ethyl}pyridin-2-yl)amino]ethyl}phenoxy)propanoate(145 mg; 57% yield). MS: m/z 737 (M+1).

Step 3.

A solution of the above intermediate (145 mg; 0.20 mmol) in 5 ml oftoluene was treated under nitrogen with azoisobutyronitrile (AIBN) (7mg; 0.039 mmol) and tributyltin hydride (0.080 ml; 0.296 mmol) and themixture heated at 80C for 1 hour. Upon cooling, additional AIBN (7 mg)and tributyltin hydride (0.080 ml) were added and the mixture heatedagain at 80C for 2 hours. The reaction mixture was concentrated and theresidue partitioned between ethyl acetate and a saturated solution ofKF. The organic phase was washed with saturated KF three times. Thecombined aqueous phases were washed twice with ethyl acetate. Thecombined organic phases were washed with 0.5N NaOH and brine, dried oversodium sulfate and concentrated. Purification by radial chromatographyusing dichloromethane-hexane mixtures (20-90%) afforded ethyl2-methyl-2-[4-(2-{[5-(2,2,2-trifluoroethyl)pyridin-2-yl][4-(trifluoromethoxy)benzyl]amino}ethyl)phenoxy]propanoate(85 mg; 73% yield).

Step 4.

The above ester was hydrolyzed with NaOH as per general procedure H.Purification by radial chromatography using ethyl acetate-hexanemixtures (20-80%) followed by methanol-dichloromethane mixtures (2-10%)afforded the title compound as a glassy solid (57 mg; 70% yield).

¹H NMR (CDCl₃) δ 8.06 (d, 1H, J=2.1), 7.34 (dd, 1H, J=8.6; 2.1), 7.15(d, 2H, J=8.6), 7.09 (d, 2H, J=8.6), 7.04 (d, 2H, J=8.1), 6.83 (d, 2H,J=8.1), 6.41 (d, 1H, J=8.6), 4.58(s, 2H), 3.66 (t, 2H, J=7.6), 3.20 (q,2H, J=10.7), 2.83 (t, 2H, J=7.6), 1.54 (s, 6H). MS: m/z 557 (M+1).

2-[4-(2-{[5-(Hydroxymethyl)pyridin-2-yl][4-(trifluoromethoxy)benzyl]amino}ethyl)phenoxy]2-methylpropanoicAcid

Step 1.

A solution of ethyl2-[4-(2-{(5-formylpyridin-2-yl)[4-(trifluoromethoxy)benzyl]amino}ethyl)phenoxy]-2-methylpropanoate(500 mg; 0.94 mmol) in 7 ml of methanol was cooled in an ice bath andtreated with sodium borohydride (65 mg; 1.7 mmol) in small portions.After 30 minutes, the reaction mixture was concentrated and the residuepartitioned between ethyl acetate and saturated brine. The organic phasewas washed with water and the combined aqueous phases reextracted withethyl acetate. The combined organic phases were washed with brine, driedover sodium sulfate and concentrated. Purification by radialchromatography using ethyl acetate-hexane mixtures (5-50% gradient)afforded ethyl2-[4-(2-{[5-(hydroxymethyl)pyridin-2-yl][4-(trifluoromethoxy)benzyl]amino}ethyl)phenoxy]-2-methylpropanoate(450 mg; 85% yield).

MS: m/z 533 (M+1).

Step 2.

The ester intermediate was hydrolyzed with NaOH as per general procedureH. Purification by radial chromatography (1-12% methanol-dichloromethanegradient), followed by crystallization from dichloromethane-hexaneafforded the title compound as a white solid.

¹H NMR (CDCl₃+CD₃OD) δ 7.96 (d, 1H, J=2.2), 7.42 (dd, 1H, J=9.0; 2.2),7.09 (d, 2H, J=8.6), 7.04 (d, 2H, J=8.6), 6.94 (d, 2H, J=8.5), 6.73 (d,2H, J=8.5), 6.38 (d, 1H, J=9.0), 4.53(s, 2H), 4.41 (s, 2H), 3.63 (t, 2H,J=7.4), 2.76 (t, 2H, J=7.4), 1.47 (s, 6H). MS: m/z 505 (M+1).

Ethyl2-methyl-2-[4-(2-{(5-nitropyridin-2-yl)[4-(trifluoromethyl)benzyl]amino}ethyl)phenoxy]propanoate

A mixture of ethyl2-methyl-2-[4-(2-{[4-(trifluoromethyl)benzyl]amino}ethyl)phenoxy]propanoate(250 mg; 0.61 mmol), 2-chloro-5-nitro-pyridine (116 mg; 0.73 mmol) andK2CO3 (126 mg; 0.92 mmol) in 2 ml of dioxane was heated at 220C in apressure tube under nitrogen for 16 hr. Upon cooling, the mixture waspartitioned between ethyl acetate and water. The aqueous phase waswashed with ethyl acetate and the combined organic phases were washedwith brine, dried over sodium sulfate and concentrated. Purification byradial chromatography using ethyl acetate-hexane mixtures (2-30%gradient) afforded the title compound (254 mg; 78% yield).

¹H NMR (CDCl₃) δ 9.03 (d, 1H, J=2.6), 8.13 (dd, 1H, J=9.3; 2.6), 7.52(d, 2H, =8.1), 7.22 (d, 2H, J=8.1), 7.01 (d, 2H, J=8.5), 6.76 (d, 2H,J=8.5), 6.39 (d, 1H, J=9.3), 4.73 (s, 2H), 4.20 (q, 2H, J=7.1), 3.76(bs, 2H), 2.87 (t, 2H, J=7.4), 1.54 (s, 6H), 122 (t, 3H, J=7.1). MS: m/z532 (M+1).

2-Methyl-2-[4-(2-{(5-nitropyridin-2-yl)[4-(trifluoromethyl)benzyl]amino}ethyl)phenoxy]propanoicAcid

Ethyl2-methyl-2-[4-(2-{(5-nitropyridin-2-yl)[4-(trifluoromethyl)benzyl]amino}ethyl)phenoxy]propanoate(80 mg) was hydrolyzed with NaOH as per general procedure H.Purification by radial chromatography (1-5% methanol-dichloromethanegradient) followed by crystallization from dichloromethane-hexaneafforded the title compound as a white solid (37 mg; 49% yield).

¹H NMR (CDCl₃) δ 9.05 (bs, 1H), 8.15 (d, 1H, J=9.3), 7.53 (d, 2H,J=8.1), 7.24 (d, 2H, J=8.1), 7.06 (d, 2H, J=8.2), 6.86 (d, 2H, J=8.2),6.39 (d, 1H, J=9.3), 4.74 (s, 2H), 3.79 (broad t, 2H), 2.90 (t, 2H,J=7.4), 1.57 (s, 6H). MS: m/z 504 (M+1).

Ethyl2-[4-(2-{(5-aminopyridin-2-yl)[4-(trifluoromethyl)benzyl]amino}ethyl)phenoxy]-2-methylpropanoate

A solution of ethyl2-methyl-2-[4-(2-{(5-nitropyridin-2-yl)[4-(trifluoromethyl)benzyl]amino}ethyl)phenoxy]propanoate(149 mg; 1.73 mmol) in 10 ml of MeOH was treated with 10% Pd/C (60 mg)and hydrogenated under balloon pressure for 2 hr. The catalyst wasfiltered off and washed with chloroform/methanol. The filtrate wasconcentrated and the residue purified by radial chromatography using amethanol-dichloromethane gradient (1-10%) to afford the title compoundas a dark-colored oil (125 mg; 89% yield).

¹H NMR (CDCl₃) δ 7.75 (d, 1H, J=2.8), 7.47 (d, 2H, J=8.1), 7.24 (d, 2H,J=8.1), 7.00 (d, 2H, J=8.5), 6.91 (d, 1H, J=9.0; 2.8), 6.74 (d, 2H,J=8.5), 6.32 (d, 1H, J=9.0), 4.58 (s, 2H), 4.20 (q, 2H, J=7.2), 3.61 (t,2H, J=7.4), 3.18 (bs, 2H), 2.80 (t, 2H, J=7.4), 1.54 (s, 6H), 1.22 (t,3H, J=7.2). MS: m/z 502 (M+1).

2-Methyl-2-[4-(2-{{5-[(methylsulfonyl)amino]pyridin-2-yl}[4-(trifluoromethyl)benzyl]amino}ethyl)phenoxy]propanoicAcid

Step 1.

A solution of ethyl2-[4-(2-{(5-aminopyridin-2-yl)[4-(trifluoromethyl)benzyl]amino}ethyl)phenoxy]-2-methylpropanoate(65 mg; 0.13 mmol) in 3 ml of dichloromethane was treated with Et₃N(0.019 ml; 0.14 mmol) and methanesulfonyl chloride (0.011 ml; 0.14mmol). After 30 minutes, additional amounts of Et₃N (0.019 ml) andmethanesulfonyl chloride (0.011 ml) were added and stirred for another30 minutes. The reaction mixture was concentrated and the residuepartitioned between ethyl acetate and 0.5N HCl. The organic phase waswashed with 0.5N HCl and brine, dried over sodium sulfate andconcentrated. Purification by radial chromatography using an ethylacetate-hexane gradient (10-70%) provided two main products: ethyl2-methyl-2-[4-(2-{{5-[(methylsulfonyl)amino]pyridin-2-yl}[4-(trifluoromethyl)benzyl]amino}ethyl)phenoxy]propanoate(10 mg; 13% yield; MS: m/z 580 (M+1)) and ethyl2-[4-(2-{{5-[bis(methylsulfonyl)amino]pyridin-2-yl}[4-(trifluoromethyl)benzyl]amino}ethyl)phenoxy]-2-methylpropanoate(39 mg; 46% yield; MS: m/z 658 (M+1)). (Both of these products can behydrolyzed to the title compound).

Step 2.

Ethyl2-[4-(2-{{5-[bis(methylsulfonyl)amino]pyridin-2-yl}[4-(trifluoromethyl)benzyl]amino}ethyl)phenoxy]-2-methylpropanoate(39 mg) was reacted with NaOH (17 eq) as per general procedure H.Purification by radial chromatography (1-10% methanol-dichloromethanegradient), followed by crystallization from dichloromethane-hexaneafforded the title compound as a white solid (21 mg; 66% yield).

¹H NMR (CDCl₃) δ 8.04 (d, 1 H, J=2.6), 7.50 (d, 2H, J=8.3), 7.42 (dd,1H, J=9.1; 2.6), 7.23 (d, 2H, J=8.3), 7.03 (d, 2H, J=8.5), 6.80 (d, 2H,J=8.5), 6.35 (d, 1H, J=9.1), 4.64 (s, 2H), 3.69 (t, 2H, J=7.4), 2.94 (s,3H), 2.83 (t, 2H, J=7.4), 1.54 (s, 6H). MS: m/z 552 (M+1).

2-[4-(2-{{5-[(Methoxycarbonyl)amino]pyridin-2-yl}[4-(trifluoromethyl)benzyl]amino}ethyl)phenoxy]-2-methylpropanoicAcid

Similarly prepared from ethyl2-[4-(2-{(5-aminopyridin-2-yl)[4-(trifluoromethyl)benzyl]amino}ethyl)phenoxy]-2-methylpropanoateand methylchloroformate.

¹H NMR (CDCl₃) δ 8.0 (d, 1H, J=2.8), 7.59 (bs, 1H), 7.48 (d, 2H, J=8.0),7.22 (d, 2H, J=8.0), 7.02 (d, 2H, J=8.4), 6.79 (d, 2H, J=8.4), 6.66 (bs,1H), 6.30 (d, 1H, J=9.2), 4.63 (s, 2H), 3.72 (s, 3H), 3.68 (t, 2H,J=7.4), 2.81 (t, 2H, J=7.4), 1.55 (s, 6H).

MS: m/z 532 (M+1).

2-[4-(2-{[5-(isopropylamino)pyridin-2-yl][4-(trifluoromethyl)benzyl]amino}ethyl)phenoxy]-2-methylpropanoicAcid

Step 1.

A solution of ethyl2-[4-(2-{(5-aminopyridin-2-yl)[4-(trifluoromethyl)benzyl]amino}ethyl)phenoxy]-2-methylpropanoate(135 mg; 0.27 mmol) in 2 ml of dichloromethane was treated with acetone(0.021 ml; 0.28 mmol), sodium triacetoxyborohydride (60 mg; 0.28 mmol)and acetic acid (0.016 ml; 0.28 mmol). After 2 hr. the reaction mixturewas partitioned between ethyl acetate and saturated NaHCO3. The organicphase was washed with brine, dried over sodium sulfate and concentrated.Purification by radial chromatography using ethyl acetate-hexanemixtures (5-50% gradient) afforded the intermediate ethyl ester (125 mg;85% yield). MS: m/z 544 (M+1).

Step 2.

A solution of the above intermediate (125 mg) in 4 ml of THF:MeOH (1:1)was treated with 1N NaOH (1 ml) and heated to 65C for 2 hr. Uponcooling, it was diluted with ethyl acetate and treated with 1N HCl (1ml). The mixture was partitioned between ethyl acetate and phosphatebuffer (pH 7). The aqueous phase was washed with ethyl acetate. Thecombined organic phases were washed with brine, dried over sodiumsulfate and concentrated to give a purple residue. Methanol was added,heated with a heat gun and the undissolved solids were removed byfiltration. The filtrate was concentrated and purified by radialchromatography using a methanol-dichloromethane gradient (1-8%). Thepartially purified product was repurified by chromatography using anethyl acetate-hexane gradient (30-100%) and subsequently crystallizedfrom dichloromethane to afford the title compound as a light grey solid(21 mg; 18% yield).

¹H NMR (CDCl₃+CD₃OD) δ 7.64 (d, 1H, J=2.8), 7.44 (d, 2H, J=8.1), 7.22(d, 2H, J=8.1), 6.92 (dd, 1H, J=9.1; 2.8), 6.87 (d, 2H, J=8.5), 6.67 (d,2H, J=8.5), 6.20 (d, 1H, J=9.1), 4.58 (s, 2H), 3.58 (t, 2H, J=7.4), 3.36(m, 1H), 2.72 (t, 2H, J=7.4), 1.48 (s, 6H), 1.12 (d, 6H, J=6.4).

1-(6-{Allyl[4-(trifluoromethoxy)benzyl]amino}pyridin-3-yl)ethanone.

Step 1.

To a solution of allylamine (17.8 g; 312 mmol) in 200 ml ofdichloromethane was added 4-trifluoromethoxybenzyl bromide (16 g; 62.4mmol) and DIEA 8.88 g; 68.4 mmol). After stirring at rt overnight thereaction mixture was extracted with one volume of water. The organicphase was dried over sodium sulfate and concentrated to affordN-[4-(trifluoromethoxy)benzyl]prop-2-en-1-amine (14 g; 97% crude yield),which was used in the next step without further purification.

¹H NMR (CDCl₃) δ 7.40 (d, 2H, J=8.4), 7.21 (d, 2H, J=8.1), 6.02-5.89 (m,1H), 5.33-5.12 (m, 2H), 3.83 (s, 2H), 3.31 (d, 2H, J=6.0).

Step 2.

A mixture of the above intermediate (7.4 g; 32.1 mmol),5-acetyl-2-chloro-pyridine (5.0 g; 32.1 mmol) and DIEA (4.56 g; 35.3mmol) was heated in a pressure tube at 200C for 3 hr. The crude reactionmixture was purified by flash chromatography using ethyl acetate-hexanemixtures (10-70% gradient) to afford the title compound (9.5 g; 84%yield).

¹H NMR (CDCl₃) δ 8.76 (d, 1H, J=2.4), 8.00 (dd, 1H, J=9.0 and 2.2), 7.23(d, 2H, J=8.3), 7.14 (d, 2H, J=8.3), 6.48 (d, 1H, J=9.1), 5.85-5.76 (m,1H), 5.27-5.15 (m, 2H), 4.84 (s, 2H), 4.12 (d, 2H, J=4.3), 2.48 (s, 3H).

4-(3-{(5-Isopropylpyridin-2-yl)[4-(trifluoromethoxy)benzyl]amino}propyl)phenol.

Step 1.

A mixture of1-(6-{allyl[4-(trifluoromethoxy)benzyl]amino}pyridin-3-yl)ethanone (10g; 28.5 mmol), 4-bromo-anisole (5.6 g; 29.9 mmol), palladium (II)acetate (0.14 g; 0.63 mmol) and tri-o-tolylphosphine (0.57 g; 1.88 mol)in 11 ml of MeCN and 8 ml of DIEA was heated to reflux overnight. Uponcooling, the mixture was concentrated and the residue partitionedbetween ethyl acetate and 1N NaOH. The organic phase was dried oversodium sulfate and concentrated. Purification by flash chromatographyeluting with dichloromethane afforded1-(6-{[(2E)-3-(4-methoxyphenyl)prop-2-enyl][4-(trifluoromethoxy)benzyl]amino}pyridin-3-yl)ethanone(7.4 g; 54% yield).

Step 2.

To a solution of methyltriphenylphosphonium bromide (11.6 g; 32.4 mmol)in dry THF was added potassium tert-butoxide (32.4 mmol of a 1M solutionin tert-butanol). After stirring at rt for 30 minutes, a solution of theabove intermediate (7.4 9) in THF was added and stirred for 2 hr. Themixture was concentrated and the residue purified by flashchromatography using 20% ethyl acetate-hexane mixtures to afford5-isopropenyl-N-[(2E)-3-(4-methoxyphenyl)prop-2-enyl]-N-[4-(trifluoromethoxy)benzyl]pyridin-2-amine.¹H NMR (CD₃OD) δ 8.18 (d, 1H, J=2.4), 7.54 (dd, 1H, J=9.0 and 2.4), 7.22(d, 2H, J=8.4), 7.15 (d, 2H, J=8.7), 7.10 (d, 2H, J=8.2), 6.71 (d, 2H,J=8.8), 6.50 (d, 1H, J=8.9), 6.33 (d, 1H, J=15.9), 6.01-5.96 (m, 1H),5.18 (s, 1H), 4.85 (s, 1H), 4.71 (s, 2H), 4.14 (d, 2H, J=5.5), 3.66 (s,3H), 1.95 (s, 3H).

Step 3.

A solution of the above intermediate (700 mg; 1.82 mmol) in ethylacetate was hydrogenated with 10% Pd/C (60 mg) under 1 atm of hydrogenfor 2 hr The catalyst was filtered off and the filtrate concentrated toafford5-isopropyl-N-[3-(4-methoxyphenyl)propyl]-N-[4-(trifluoromethoxy)benzyl]pyridin-2-amine,which was used in the next step without further purification.

Step 4.

The above intermediate was demethylated with boron tribromide as pergeneral procedure F. After standard aqueous workup the tittle compoundwas obtained, which was used in the next step without furtherpurification.

3-(3-{(5-Isopropylpyridin-2-yl)[4-(trifluoromethoxy)benzyl]amino}propyl)phenol.

Similarly prepared from1-(6-{allyl[4-(trifluoromethoxy)benzyl]amino}pyridin-3-yl)ethanone and3-bromo-anisole.

2-[4-(3-{(5-Isopropylpyridin-2-yl)[4-(trifluoromethoxy)benzyl]amino}propyl)phenoxy]-2-methylpropanoicAcid

Step 1.

Alkylation of4-(3-{(5-isopropylpyridin-2-yl)[4-(trifluoromethoxy)benzyl]amino}propyl)phenol(410 mg; 0.78 mmol) with ethyl-2-bromo-isobutyrate (300 mg; 1.56 mmol)as per general procedure C (2 eq Cs2CO3, MeCN, 80C) provided theintermediate ethyl ester.

Step 2.

Hydrolysis of the above intermediate with LiOH as per general procedureH afforded after chromatography the title compound (92 mg; 35% yield).

¹H NMR (CD₃O D) δ 7.84 (d, 1H, J=2.2), 7.45 (dd, 1H, J=8.9 and 2.3),7.24 (d, 2H, J=8.4), 7.17 (d, 2H, J=8.4), 7.02 (d, 2H, J=8.4), 6.80 (d,2H, J=8.6), 6.53 (d, 1H, J=8.8), 4.71 (s, 2H), 3.46 (t, 2H, J=7.5),2.81-2.75 (m, 1H), 2.56 (t, 2H, J=7.5), 1.89-1.83 (m, 2H), 1.51 (s, 6H),1.19 (d, 6H, J=6.9). MS: m/z 531 (M+1).

2-[3-(3-{(5-Isopropylpyridin-2-yl)[4-(trifluoromethoxy)benzyl]amino}propyl)phenoxy]-2-methylpropanoicAcid

Similarly prepared by alkylation of3-(3-{(5-isopropylpyridin-2-yl)[4-(trifluoromethoxy)benzyl]amino}propyl)phenolwith ethyl-2-bromo-isobutyrate followed by standard base-mediatedhydrolysis.

¹H NMR (CD₃OD) δ 7.84 (d, 1H, J=2.2), 7.51-7.45 (m, 1H), 7.25-7.08 (m,5H), 6.80-6.69 (m, 3H), 6.56 (d, 1H, J=9.0), 4.72 (s, 2H), 3.47 (t, 2H,J=7.6), 2.80-2.75 (m, 1H), 2.58 (t, 2H, J=7.3), 1.91-1.85 (m, 2H), 1.52(s, 6H), 1.21 (d, 6H, J=6.9). MS: m/z 531 (M+1).

[4-(3-{(5-Isopropylpyridin-2-yl)[4-(trifluoromethoxy)benzyl]amino}propyl)phenoxy]aceticAcid

Similarly prepared by alkylation of4-(3-{(5-isopropylpyridin-2-yl)[4-(trifluoromethoxy)benzyl]amino}propyl)phenolwith tert-butyl-bromo-acetate followed by standard TFA hydrolysis.

¹H NMR (CD₃OD) δ 7.98 (dd, 1H, J=9.5 and 2.2), 7.65 (d, 1H, J=2.0),7.34-7.22 (m, 4H), 7.11-7.09 (m, 3H), 6.83 (d, 2H, J=8.6), 4.82 (s, 2H),4.62 (s, 2H), 3.61 (t, 2H, J=7.6), 2.92-2.88 (m, 1H), 2.63 (t, 2H,J=7.5), 1.99-1.95 (m, 2H), 1.23 (d, 6H, J=6.9). MS: m/z 503 (M+1).

[3-(3-{(5-Isopropylpyridin-2-yl)[4-(trifluoromethoxy)benzyl]amino}propyl)phenoxy]aceticAcid

Similarly prepared by alkylation of3-(3-{(5-isopropylpyridin-2-yl)[4-(trifluoromethoxy)benzyl]amino}propyl)phenolwith tert-butyl-bromo-acetate followed by standard TFA hydrolysis.

¹H NMR (CD₃OD) δ 7.98 (dd, 1H, J=9.0 and 2.2), 7.68 (d, 1H, J=1.8),7.32-7.10 (m, 7H), 6.80-6.74 (m, 2H), 4.83 (s, 2H), 4.63 (s, 2H), 3.64(t, 2H, J=7.7), 2.93-2.90 (m, 1H), 2.68 (t, 2H, J=7.4), 2.06-1.99 (m,2H), 1.24 (d, 6H, J=6.8). MS: m/z 503 (M+1).

The following 14 compounds were prepared by procedures similar to thosedescribed above.

2-[4-(2{(5-isopropenylpyridin-2-yl)[4-(trifluoromethoxy)benzyl]amino}ethyl)phenoxy]-2-methylpropanoicAcid

2-[2-bromo-4-(2-{(5-isopropylpyridin-2-yl)[4-(trifluoromethoxy)benzyl]amino}ethyl)phenoxy]-2-methylpropanoicAcid

[4-(2-{(5-isopropylpyridin-2-yl)[4-(trifluoromethoxy)benzyl]amino}ethyl)-2-methylphenoxy]aceticAcid

2-[4-(2-{(3-methoxypyridin-2-yl)[4-(trifluoromethoxy)benzyl]amino}ethyl)phenoxy]-2-methylpropanoicAcid

2-[4-(2-{(3-isopropoxypyridin-2-yl)[4-(trifluoromethoxy)benzyl]amino}ethyl)phenoxy]-2-methylpropanoicAcid

2-[4-(2-{[5-(isopropylamino)pyridin-2-yl][4-(trifluoromethoxy)benzyl]amino}ethyl)phenoxy]-2-methylpropanoicAcid

2-[4-(2-{[5-(dimethylamino)pyridin-2-yl][4-(trifluoromethoxy)benzyl]amino}ethyl)phenoxy]-2-methylpropanoicAcid

2-[4-(2-{[5-(methoxymethyl)pyridin-2-yl][4-(trifluoromethoxy)benzyl]amino}ethyl)phenoxy]-2-methylpropanoicAcid

MS: m/z 519.5 (M+1)

2-[4-(1,1-dimethyl-2-{(5-methylpyridin-2-yl)[4-(trifluoromethoxy)benzyl]amino}ethyl)phenoxy]-2-methylpropanoicAcid

MS: m/z 517.5 (M+1)

2-[4-(1,1-dimethyl-2-{pyridin-2-yl[4-(trifluoromethoxy)benzyl]amino}ethyl)-2-propylphenoxy]-2-methylpropanoicAcid

[4-(1,1-dimethyl-2-{pyridin-2-yl[4-(trifluoromethoxy)benzyl]amino}ethyl)-2-propylphenoxy]aceticAcid

2-methyl-2-[4-(3-{[4-(trifluoromethoxy)benzyl][5-(trifluoromethyl)pyridin-2-yl]amino}propyl)phenoxy]propanoicAcid

2-[4-(3-{(5-isopropylpyridin-2-yl)[4-(trifluoromethyl)benzyl]amino}propyl)phenoxy]-2-methylpropanoicAcid

2-[4-(3-{(5-isopropylpyridin-2-yl)[3-(trifluoromethoxy)benzyl]amino}propyl)phenoxy]-2-methylpropanoicAcid

2-[4-(2-{(6-Chloropyridazin-3-yl)[4-(trifluoromethyl)benzyl]amino}ethyl)phenoxy]-2-methylpropanoicAcid

Step 1.

Ethyl2-methyl-2-[4-(2-{[4-(trifluoromethyl)benzyl]amino}ethyl)phenoxy]propanoate(200 mg; 0.49 mmol) was condensed with 3,6-dichloropyridazine (87 mg;0.61 mmol) as per general procedure E (conditions: 1.25 eq DIEA,dioxane, 220C, 6 hr). Purification by radial chromatography (5-40% ethylacetate-hexane gradient) afforded the intermediate ethyl ester (60 mg;24% yield). MS: m/z 522 (M+1).

Step 2.

The above ester (60 mg) was hydrolyzed with NaOH as per generalprocedure H. Standard aqueous workup followed by crystallization fromdichloromethane-hexane afforded the title compound as a white solid (39mg; 68% yield).

¹H NMR (CDCl₃) δ 7.50 (d, 2H, J=8.1), 7.24 (d, 2H, J=8.1), 7.09 (d, 1H,J=9.4), 7.02 (d, 2H, J=8.3), 6.82 (d, 2H, J=8.3), 6.58 (d, 1H, J=9.4),4.65 (s, 2H), 3.76 (t, 2H, J=7.1), 2.86 (t, 2H, J=7.1), 1.54 (s, 6H).MS: m/z 494 (M+1).

2-(4-{2-[[2,4-Bis(trifluoromethyl)benzyl](6-chloropyridazin-3-yl)amino]ethyl}phenoxy)-2-methylpropanoicAcid

Similarly prepared from methyl2-[4-(2-{[2,4-bis(trifluoromethyl)benzyl]amino}ethyl)phenoxy]-2-methylpropanoateand 3,6-dichloropyridazine.

¹H NMR (CDCl₃) δ 7.90 (s, 1H), 7.65 (d, 1H, J=8.1), 7.31 (d, 1H, J=8.1),7.14 (d, 1H, J=9.5), 7.08 (d, 2H, J=8.5), 6.85 (d, 2H, J=8.5), 6.56 (d,1H, J=9.5), 4.84 (s, 2H), 3.79 (t, 2H, J=7.1), 2.94 (t, 2H, J=7.1), 1.55(s, 6H). MS: m/z 562 (M+1).

2-Methyl-2-[4-(2-{pyrazin-2-yl[4-(trifluoromethyl)benzyl]amino}ethyl)phenoxy]propanoicAcid

Similarly prepared from ethyl2-methyl-2-[4-(2-{[4-(trifluoromethyl)benzyl]amino}ethyl)phenoxy]propanoateand chloropyrazine.

¹H NMR (CDCl₃) δ 8.08 (bs, 1H), 7.91 (bs, 1H), 7.77 (bs, 1H), 7.51 (d,2H, J=8.1), 7.24 (d, 2H, J=8.1), 7.02 (d, 2H, J=8.4), 6.83 (d, 2H,J=8.4), 4.67 (s, 2H), 3.68 (t, 2H, J=7.2), 2.83 (t, 2H, J=7.2), 1.56 (s,6H). MS: m/z 488 (M+1).

2-[4-(2-{1,3-Benzoxazol-2-yl[4-(trifluoromethyl)benzyl]amino}ethyl)phenoxy]-2-methylpropanoicAcid

Step 1.

Ethyl2-methyl-2-[4-(2-{[4-(trifluoromethyl)benzyl]amino}ethyl)phenoxy]propanoate(150mg; 0.37 mmol) was condensed with 2-chloro-benzoxazole (0.046 ml; 0.40mmol) as per procedure E (conditions: 1.1 eq DIEA; dioxane, 200C, 16hr). Purification by radial chromatography (5-50% ethyl acetate-hexanegradient) afforded the intermediate ester (170 mg; 88% yield). MS: m/z527 (M+1).

Step 2.

The above ester (170 mg) was hydrolyzed with NaOH as per procedure H.Purification by radial chromatography (1-10% methanol-dichloromethanegradient), followed by crystallization from dichloromethane-hexaneafforded the title compound as a white solid (132 mg; 83% yield).

¹H NMR (CDCl₃) δ 7.51 (d, 2H, J=8.1), 7.42 (d, 1H, J=7.8), 7.27 (m, 3H),7.16 (t, 1H, J=7.8), 7.02 (m, 3H), 6.82 (d, 2H, J=8.5), 4.60 (s, 2H),3.65 (t, 2H, J=7.2), 2.85 (t, 2H, J=7.2), 1.54 (s, 6H). MS: m/z 499(M+1).

2-[4-(2-{1,3-Benzoxazol-2-yl[2,4-bis(trifluoromethyl)benzyl]amino}ethyl)phenoxy]-2-methylpropanoicAcid

Similarly prepared from methyl2-[4-(2-{[2,4-bis(trifluoromethyl)benzyl]amino}ethyl)phenoxy]-2-methylpropanoateand 2-chlorobenzoxazole.

¹H NMR (CDCl₃) δ 7.89 (s, 1H), 7.69 (d, 1H, J=8.1), 7.48 (d, 1H, J=8.1),7.42 (d, 1H, J=7.7), 7.24 (d, 1H, J=8.0), 7.17 (t, 1H, J=7.7), 7.04 (m,3H), 6.81 (d, 2H, J=8.5), 4.87 (s, 2H), 3.70 (t, 2H, J=7.2), 2.92 (t,2H, J=7.2), 1.53 (s, 6H). MS: m/z 567 (M+1).

2-[4-(2-{1,3-Benzoxazol-2-yl[4-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)benzyl]amino}ethyl)phenoxy]-2-methylpropanoicAcid

Similarly prepared from ethyl2-[4-(2-{[4-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)benzyl]amino}ethyl)phenoxy]-2-methylpropanoateand 2-chlorobenzoxazole.

¹H NMR (CDCl₃) δ 7.91 (d, 2H, J=8.1), 7.42 (d, 1H, J=7.6), 7.24 (m, 3H),7.15 (t, 1H, J=7.6), 7.04 (t, 1 H, J=7.6), 6.96 (d, 2H, J=8.5), 6.77 (d,2H, J=8.5), 4.61 (s, 2H), 3.66 (t, 2H, J=7.2), 2.84 (t, 2H, J=7.2), 2.22(m, 1 H), 1.53 (s, 6H), 1.24 (m, 4H). MS: m/z 567 (M+1).

2-[3-(3-{1,3-Benzoxazol-2-yl[4-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)benzyl]amino}propyl)phenoxy]-2-methylpropanoicAcid

Condensation of tert-butyl2-[3-(3-{[4-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)benzyl]amino}propyl)phenoxy]-2-methylpropanoatewith 1.5 eq of 2-chlorobenzoxazole, as per general procedure E(conditions: 3 eq DIEA, THF, 100C, 8 hr), followed by standard TFAhydrolysis (general procedure 1) provided the title compound.

¹H NMR (CDCl₃) δ 7.96 (d, 2H, J=8.2), 7.44 (d, 1H, J=7.9), 7.29 (d, 2H,J=8.2), 7.27 (d, 1H, J=7.9), 7.20 (t, 1H, J=7.4), 7.12 (t, 1H, J=7.7),7.08 (t, 1H, J=7.7), 6.75 (m, 3H), 4.75 (s, 2H), 3.46 (t, 2H, J=7.9),2.56 (t, 2H, J=7.0), 2.26 (m, 1H), 1.92 (m, 2H), 1.63 (s, 6H), 1.26 (m,4H). MS: m/z 553 (M+1).

2-[3-(3-{1,3-Benzoxazol-2-yl[4-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)benzyl]amino}propyl)phenoxy]-2-methylpropanoicAcid

Similarly prepared from tert-butyl2-[3-(3-{[2,4-bis(trifluoromethyl)benzyl]amino}propyl)phenoxy]-2-methylpropanoateand 2-chlorobenzoxazole.

¹H NMR (CDCl₃) δ 7.93 (s, ₁H), 7.71 (d, 1H, J=8.2), 7.46 (d, 1H, J=8.2)7.38 (d, 1H, J=7.8), 7.19 (d, 1H, J=7.9), 7.16 (t, 1H, J=7.8), 7.09 (t,1H, J=7.7), 7.01 (t, 1H, J=7.8), 6.76 (m, 3H), 4.96 (s, 2H), 3.49 (t,2H, J=7.8), 2.59 (t, 2H, J=6.6), 1.95 (m, 2H), 1.57 (s, 6H). MS: m/z 581(M+1).

The following 7 compounds were prepared using procedures similar tothose described above.

2-(4-{2-[1,3-benzoxazol-2-yl(4-cyanobenyl)amino]ethyl}phenoxy)-2-methylpropanoicAcid

MS: m/z 456.2 (M+1)

2-[4-(2-{1,3-benzoxazol-2-yl[4-(1,2,4-oxadiazol-3-yl)benzyl]amino}ethyl)phenoxy]-2-methylpropanoicAcid

2-[4-(2-{1,3-benzoxazol-2-yl[4-(5-methyl-1,2,4-oxadiazol-3-yl)benzyl]amino}ethyl)phenoxy]-2-methylpropanoicAcid

2-{4-[2-(1,3-benzoxazol-2-yl{4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]benzyl}amino)ethyl]phenoxy}-2-methylpropanoicAcid

MS: m/z 566.9 (M+1)

2-{4-[2-(1,3-benzoxazol-2-yl{4-[5-(methylamino)-1,2,4-oxadiazol-3-yl]benzyl}amino)ethyl]phenoxy}-2-methylpropanoicAcid

MS: m/z 528.2 (M+1)

2-{4-[2-(1,3-benzoxazol-2-yl{4-[5-(dimethylamino)-1,2,4-oxadiazol-3-yl]benzyl}amino)ethyl]phenoxy}-2-methylpropanoicAcid

MS: m/z 542 (M+1)

2-[4-(2-{1,3-benzoxazol-2-yl[4-(trifluoromethoxy)benzyl]amino}-1,1-dimethylethyl)phenoxy]-2-methylpropanoicAcid

MS: m/z 543.1 (M+1)

2-[4-(2-{1,3-Benzothiazol-2-yl[4-(trifluoromethyl)benzyl]amino}ethyl)phenoxy]-2-methylpropanoicAcid.

Similarly, condensation of ethyl2-methyl-2-[4-(2-{[4-(trifluoromethyl)benzyl]amino}ethyl)phenoxy]propanoatewith 2-chlorobenzothiazole, followed by standard hydrolysis with NaOHafforded the title compound.

¹H NMR (CDCl₃) δ 7.56 (d, 2H, J=8.1), 7.52 (d, 2H, J=8.1), 7.30 (m, 3H),7.05 (m, 3H), 6.85 (d, 2H, J=8.5), 4.65 (s, 2H), 3.64 (t, 2H, J=7.3),2.91 (t, 2H, J=7.3), 1.54 (s, 6H). MS: m/z 515 (M+1).

2-[4-(2-{(6-Methoxy-1,3-benzothiazol-2-yl)[4-(trifluoromethyl)benzyl]amino}ethyl)phenoxy]-2-methylpropanoicAcid

Similarly prepared from ethyl2-methyl-2-[4-(2-{[4-(trifluoromethyl)benzyl]amino}ethyl)phenoxy]propanoateand 2-chloro-6-methoxy benzothiazole.

¹H NMR (CDCl₃) δ 7.52 (d, 2H, J=7.9), 7.46 (d, 1H, J=8.8), 7.29 (d, 2H,J=7.9), 7.10 (d, 1H, J=2.1), 7.04 (d, 2H, J=8.3), 6.88 (dd, 1H, J=8.8;2.1), 6.84 (d, 2H, J=8.3), 4.62 (s, 2H), 3.79 (s, 3H), 3.61 (t, 2H,J=7.1), 2.90 (t, 2H, J=7.1), 1.54 (s, 6H).

2-[4-(2-{(6-Chloro-1,3-benzothiazol-2-yl)[4-(trifluoromethyl)benzyl]amino}ethyl)phenoxy]-2-methylpropanoicAcid

Similarly prepared from ethyl2-methyl-2-[4-(2-{[4-(trifluoromethyl)benzyl]amino}ethyl)phenoxy]propanoateand 2,6-dichloro benzothiazole. ¹H NMR (CDCl₃) δ 7.55 (d, 2H, J=8.0),7.52 (d, 1 H, J=2.0), 7.47 (d, 1H, J=8.0), 7.32 (d, 2H, J=8.0), 7.24(dd, 1H, J=8.0; 2.0), 7.07 (d, 2H, J=8.6), 6.86 (d, 2H, J=8.6), 4.67 (s,2H), 3.65 (t, 2H, J=7.2), 2.93 (t, 2H, J=7.2), 1.53 (s, 6H). MS: m/z 549(M+1).

2-(4-{2-[[2,4-Bis(trifluoromethyl)benzyl](6-chloro-1,3-benzothiazol-2-yl)amino]ethyl}phenoxy)-2-methylpropanoicAcid

Similarly prepared from methyl2-[4-(2-{[2,4-bis(trifluoromethyl)benzyl]amino}ethyl)phenoxy]-2-methylpropanoateand 2,6-dichloro benzothiazole.

¹H NMR (CDCl₃) δ 7.89 (s, 1H), 7.68 (d, 1H, J=8.1), 7.54 (d, 1H, J=2.1),7.47 (d, 1 H, J=8.1), 7.43 (d, 1H, J=8.6), 7.22 (dd, 1H, J=8.6; 2.1),7.06 (d, 2H, J=8.5), 6.84 (d, 2H, J=8.5), 4.88 (s, 2H), 3.64 (t, 2H,J=7.4), 2.94 (t, 2H, J=7.4), 1.54 (s, 6H). MS: m/z 617 (M+1).

2-(3-{3-[[4-(5-Cyclopropyl-1,2,4-oxadiazol-3-yl)benzyl](5-phenyl-1,3-oxazol-2-yl)amino]propyl}phenoxy)-2-methylpropanoicAcid

Similarly prepared from tert-butyl2-[3-(3-{[4-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)benzyl]amino}propyl)phenoxy]-2-methylpropanoateand 2-chloro-5-phenyl-oxazole (ref. GB1552125).

¹H NMR (CDCl₃) δ 7.98 (d, 2H, J=8.1), 7.41-7.28 (m, 6H), 7.24-7.1 (m,3H), 6.8-6.71 (m, 3H), 4.68 (s, 2H), 3.39 (broad t, 2H), 2.59 (broad t,2H), 2.28-2.22 (m, 1H), 1.96-1.86 (m, 2H), 1.63 (s, 6H), 1.3-1.24 (m,4H). MS: m/z 579 (M+1).

4-(4-bromophenyl)-2-cyclopropyl-1,3-oxazole

Step 1.

To a slurry of sodium carbonate (9.00 g, 84.91 mmol) in DMF (100 ml) wasadded dropwise cyclopropane carboxylic acid (4.5 ml, 56.50 mmol).Themixture was stirred for 15 min and then treated with2,4′-dibromoacetophenone (15.71 g, 56.52 mmol). After 3 h, the mixturewas partitioned between Et₂O and water. The aqueous phase was extractedwith Et₂O (4×125 ml). The combined organic phases were dried over MgSO₄and concentrated in vacuo to yield 2-(4-bromophenyl)-2-oxoethylcyclopropane carboxylate as a yellow solid (15.81 g, 98%).

¹H NMR (CDCl₃) δ 7.75 (d, 2H, J=8.5), 7.60 (d, 2H, J=8.6), 5.26 (s, 2H),1.77 (m, 1H), 1.09-1.06 (m, 2H), 0.96-0.93 (m, 2H).

Step 2. To a mixture of 2-(4-bromophenyl)-2-oxoethyl cyclopropanecarboxylate (6.00 g, 21.19 mmol) and acetamide (6.60 g, 111.73 mmol) wasadded BF₃/Et₂O (4 ml). The mixture was heated to 140C for 2.5 h. Uponcooling, water was added, and the mixture was extracted with Et₂O (4×125ml). The combined organic phases were dried with MgSO₄ and concentratedin vacuo. The crude material was purified by flash chromatography(CH₂Cl₂/hexanes, 7:3) to provide the title compound as a yellow solid(3.61 g, 64%).

¹H NMR (CDCl₃) δ 7.71 (s, 1H), 7.54 (d, 2H, J=8.4), 7.47 (d, 2H, J=8.6),2.08 (s, 1H), 1.11-1.00 (m, 4H).

3-(4-bromophenyl)-5-cyclopropylisoxazole

Step 1.

To a 0C solution of benzotriazole (5.05 g, 42.39 mmol) in CH₂Cl₂ (100mL) was added dropwise triethylamine (9.0 ml, 64.57 mmol) followed bycyclopropyl carbonyl chloride is (4.2 ml, 46.28 mmol). The mixture wasstirred at rt for 1 h and then quenched with a solution of 2N aqueousHCl (75 ml). The organic phase was washed with 2 N HCl (2×75 mL) andwater (100 ml), dried with MgSO₄ and concentrated in vacuo. The solidresidue was washed with hexenes, filtered and dried to yield1-(cyclopropylcarbonyl)-1H-1,2,3-benzotriazole as a white solid (5.92 g,75%).

Step 2.

To a −78C solution of LDA (generated from 8 ml of 2.5 M nBuLi and 2.1 mlof diisopropylamine) in THF (120 ml) was added dropwise, over 80 min, asolution a 4′-bromoacetophenone (2.98 g, 14.97 mmol) in THF (45 ml). Themixture continued to stir at −78C for 1 h, followed by addition of1-(cyclopropylcarbonyl)-1H-1,2,3-benzotriazole (2.56 g, 13.65 mmol) inTHF (45 ml). The mixture was warmed to rt overnight. The yellow mixturewas poured into water and extracted with Et₂O (2×300 ml). The combinedorganic phases were washed with water, dried with MgSO₄, andconcentrated in vacuo. The crude material was purified by flashchromatography (CH₂Cl₂/hexanes, 10:90 to 30:70) to yield1-(4-bromophenyl)-3-cyclopropyl-1,3-propanedione as an orange solid(1.60 g, 44%).

¹H NMR (CDCl₃) δ 7.70 (d, 2H, J=8.6), 7.55 (d, 2H, J=8.4), 6.23 (s, 1H),1.78 (m, 1H), 1.20-1.16 (m, 2H), 1.00-0.95 (m, 2H).

Step 3. To a solution of1-(4-bromophenyl)-3-cyclopropyl-1,3-propanedione (2.60 g, 9.73 mmol) inanhydrous MeOH (80 ml) was added hydroxylamine hydrochloride (2.71g,39.00 mmol). The mixture was heated to reflux for 14 h. Upon cooling,the solution was poured into water, and extracted with CH₂Cl₂ (3×200ml). The combined organic phases were dried with MgSO₄ and concentratedin vacuo. The regioisomers were separated by flash chromatography(CH₂Cl₂/hexanes, 10:90 to 40:60) to yield the title compound as a whitesolid (1.04 g, 40%).

¹H NMR (CDCl₃) δ 7.67 (d, 2H, J=8.5), 7.60 (d, 2H, J=8.5), 6.22 (s, 1H),2.11 (m, 1H), 1.17-1.03 (m, 4H).

2-(4-bromophenyl)-4-cyclopropyl-1,3-oxazole

Step 1.

To a cooled solution of cyclopropylmethyl ketone (7.0 ml, 70.65 mmol) inMeOH (40 mL) was added dropwise bromine (3.6 mL, 70.28 mmol) over a 2 hperiod. The mixture was stirred for 30 min at rt, followed by additionof water. The mixture was extracted with Et₂O (4×150 ml). The combinedorganic phases were washed with a solution of 10% aqueous Na₂CO3, waterand brine, dried with Na₂CO3 and concentrated in vacuo. The crudematerial was purified by distillation in vacuo (44-47C) to yield2-bromo-1-cyclopropylethanone (9.69 g, 85%).

¹H NMR (CDCl₃) δ 3.99 (s, 2H), 2.19 (m, 1H), 1.13-1.09 (m, 2H),1.02-0.97 (m, 2H).

Step 2.

To a solution of bromobenzoic acid (9.97 g, 49.60 mmol) in DMF (65 mL)was added Na₂CO3 (7.90 g, 74.54 mmol). After stirring for 15 min,2-bromo-1-cyclopropylethanone (9.69 g, 59.44 mmol) was added, and themixture was stirred at rt for 12 h. Water was added, and the mixture wasextracted with Et₂O (6×125 ml). The combined organic phases were driedwith MgSO₄ and concentrated in vacuo. Recrystallization from EtOHyielded 2-cyclopropyl-2-oxoethyl 4-bromobenzoate as white needles (8.53g, 61%).

¹H NMR (CDCl₃) δ 7.93 (d, 2H, J=8.8), 7.57 (d, 2H, J=8.8), 5.03 (s, 2H),1.98 (m, 1H), 1.16-1.12 (m, 2H), 1.00-0.96 (m, 2H).

Step 3.

To a mixture of 2-cyclopropyl-2-oxoethyl 4-bromobenzoate (4.51 g, 15.93mmol) and acetamide (4.71 g, 79.74 mmol) was added BF₃/Et₂O (1 ml). Themixture was heated at 140C for 8 h. Upon cooling, the mixture waspartitioned between water and Et₂O. The aqueous phase was extracted withEt₂O (1×125 ml). The combined organic phases were washed with Water andbrine, dried with MgSO₄, and concentrated in vacuo. The crude materialwas purified by flash chromatography (CH₂Cl₂/hexanes, 30:70 to 50:50) toyield the title compound as a white crystalline solid (0.69 g, 16%).

¹H NMR (CDCl₃, 400 M): δ 7.84 (d, 2H, J=8.8), 7.53 (d, 2H, J=8.8), 7.40(s, 1H), 1.81 (m, 1H), 0.91-0.86 (m, 2H), 0.81-0.77 (m, 2H).

4-(2-Cyclopropyl-1,3-oxazol-4-yl)benzaldehyde

Step 1.

To a solution of 4-(4-bromophenyl)-2-cyclopropyl-1,3-oxazole (1.78 g,6.74 mmol) in NMP (25 mL) was added copper cyanide (4.22 g, 47.12 mmol).The mixture was heated to 185C for 4 h. Upon cooling, the mixture waspoured into a OC solution of 5% aqueous sodium cyanide (60 ml). Theaqueous phase was extracted with Et₂O. The combined organic phases werewashed with, 5% aqueous sodium cyanide, water, and brine, dried withMgSO₄ and concentrated in vacuo. The crude material was purified byflash chromatography (CH₂Cl₂/Hexanes, 2:3 to 10:0) to yield4-(2-cyclopropy-1,3-oxazol-4-yl)benzonitrile as a yellow solid (1.00 g,71%).

¹H NMR (CDCl₃) δ 7.82 (s, 1H), 7.77 (d, 2H, J=8.3), 7.64 (d, 2H, J=8.3),2.10 (m, 1H), 1.13-1.03 (m, 4H).

Step 2.

To a 0C solution of 4-(2-cyclopropyl-1,3-oxazol-4-yl)benzonitrile (0.984g, 4.68 mmol) in anhydrous CH₂Cl₂ (3 ml) was added dropwise a 1 Msolution of DIBAL in CH₂Cl₂ (5.60 ml, 1.22 mmol). Upon completion ofaddition, the solution was warmed to 45C for 3 h. The solution wascooled and 10% aqueous H₂SO₄ was slowly added until pH<4. The mixturewas stirred overnight at rt. The aqueous phase was extracted with CH₂Cl₂(3×40 ml). The combined organic phases were dried with MgSO₄ andconcentrated in vacuo. The crude material was purified by flashchromatography (EtOAc/hexanes, 1:4) to yield the title compound as ayellow solid (0.92 g, 92%).

¹H NMR (CDCl₃) δ 9.98 (s, 1H), 7.89-7.83 (m, 4H), 7.84 (s, 1H), 2.11 (m,1H), 1.14-1.03 (m, 4H).

4-(3-cyclopropyl-5-isoxazolyl)benzaldehyde

Similarly prepared from 3-(4-bromophenyl)-5-cyclopropylisoxazole.

¹H NMR (CDCl₃) δ 10.03 (s, 1H), 7.93 (d+d, 4H), 6.25(s, 1H), 2.08 (m,1H), 1.11-1.01 (m, 4H).

4-(4-Cyclopropyl-1,3-oxazol-2-yl)benzaldehyde

Similarly prepared from 2-(4-bromophenyl)-4-cyclopropyl-1,3-oxazole.

¹H NMR (CDCl₃) δ 10.03 (s, 1H), 8.14 (d, 2H, J=8.2), 7.92 (d, 2H,J=8.5), 7.47 (s, 1H), 1.84 (m, 1 H), 0.93-0.80 (m, 4H).

2-{4-[2-([4-(2-cyclopropyl-1,3-oxazol-4-yl)benzyl]{5-[3-(trifluoromethyl)phenyl]-1,2,4-oxadiazol-3-yl}amino)ethyl]phenoxy}-2-methylpropanoicAcid

Step 1.

To a solution of 4-(2-cyclopropyl-1,3-oxazol-4-yl)benzaldehyde (0.318 g,1.49 mmol) in MeOH (5 ml) was added tyramine (0.215 g, 1.57 mmol) andtrimethylorthoformate (1.2 mL, 10.97 mmol). The resulting solid wasredissolved in THF (3 ml) and allowed to stir for 12 h. Sodiumborohydride (0.15 g, 3.94 mmol) was added and the mixture was stirred anadditional 2 h. The reaction mixture was concentrated and partitionedbetween EtOAc and water. The aqueous phase was extracted with EtOAc andthe combined organic phases were washed with brine, dried with MgSO₄,and concentrated in vacuo. The crude material was purified by flashchromatography (MeOH/CH₂Cl₂, 5:95 to 10:90) to yield4-(2-{[4-(2-cyclopropyl-1,3-oxazol-4-yl)benzyl]amino}ethyl)phenol as awhite solid (0.43 g, 85%).

¹H NMR (DMSO-d₆) δ 9.08 (s, 1H), 8.32 (s, 1H), 7.60 (d, 2H, J=8.1), 7.28(d, 2H, J=7.9), 6.93 (d, 2H, J=8.3), 6.60 (d, 2H, J=8.3), 3.66 (s, 2H),2.61-2.56 (m, 4H), 2.10 (m, 1H), 1.03-0.92 (m, 4H).

Step 2.

To a warm solution of4-(2-{[4-(2-cyclopropyl-1,3-oxazol-4-yl)benzyl]amino}ethyl)phenol (0.42g, 1.25 mmol) in acetonitrile (6 ml) was added Cs2CO3 (1.34 g, 4.11mmol) followed by ethyl-2-bromoisobutyrate (0.60 mL, 4.09 mmol). Themixture was heated at 80C for 20 h. Upon cooling, the mixture waspartitioned between EtOAc and water. The aqueous phase was extractedwith EtOAc (2×25 ml). The combined organic phases were dried with MgSO₄and concentrated in vacuo. The crude material was purified by flashchromatography (MeOH/EtOAc, 2:98) to yield ethyl2-[4-(2-{[4-(2-cyclopropyl-1,3-oxazol-4-yl)benzyl]amino}ethyl)phenoxy]-2-methylpropanoate(0.42 g, 74%).

¹H NMR (CDCl₃) δ 7.68 (s, 1H), 7.60 (d, 2H, J=8.1), 7.26 (d, 2H, J=8.1),7.02 (d, 2H, J=8.4), 6.74 (d, 2H, J=8.5), 4.20 (q, 2H, J=7.2), 3.78 (s,2H), 2.83 (t, 2H, J=7.1), 2.74 (t, 2H, J=6.5), 2.02 (m, 1H), 1.54 (s,6H), 1.22 (t, 3H, J=5.5), 1.10-1.01 (m, 4H).

Step 3.

To a 0C solution of ethyl2-[4-(2-{[4-(2-cyclopropyl-1,3-oxazol-4-yl)benzyl]amino}ethyl)phenoxy]-2-methylpropanoate(0.42 g, 0.92 mmol) in anhydrous CH₂Cl₂ (9 ml) was added dropwisetriethylamine (0.16 ml, 1.15 mmol) followed by a 3M solution of cyanogenbromide in CH₂Cl₂ (0.37 ml, 1.11 mmol). The mixture was stirred at rtfor 2 h. The reaction mixture was concentrated in vacuo, and the residuewas partitioned between CH₂Cl₂ and water. The aqueous phase wasextracted with CH₂Cl₂ (2×20 ml). The combined organic phases were washedwith brine, dried with MgSO₄, and concentrated in vacuo. The crudematerial was purified by flash chromatography (EtOAc/hexanes, 25:75 to35:65) to yield ethyl2-(4-(2-{cyano[4-(2-cyclopropyl-1,3-oxazo[4-yl)benzyl]amino}ethyl)phenoxy]-2-methylpropanoate(0.39 g, 89%).

¹H NMR (CDCl₃) δ 7.74 (s, 1H), 7.65 (d, 2H, J=8.1), 7.21 (d, 2H, J=8.1),7.00 (d, 2H, J=8.6), 6.75 (d, 2H, J=8.5), 4.20 (q, 2H, J=7.1), 4.09 (s,2H), 3.08 (t, 2H, J=7.1), 2.83 (t, 2H, J=7.8), 2.10 (m, 1H), 1.55 (s,6H), 1.22 (t, 3H), 1.11-1.03 (m, 4H).

Step 4.

To a solution of ethyl2-[4-(2-{cyano[4-(2-cyclopropyl-1,3-oxazol-4-yl)benzyl]amino}ethyl)phenoxy]-2-methylpropanoate(0.38 g, 0.80 mmol; in DMF (2 ml) was added hydroxylamine hydrochloride(0.20 g, 2.94 mmol) followed by sodium acetate (2.88 g, 3.59 mmol). Themixture was stirred at rt for 12 h. The reaction mixture was partitionedbetween EtOAc and water. The aqueous phase was extracted with EtOAc(2×20 ml). The combined organic phases were washed with brine, driedwith MgSO₄, and concentrated in vacuo to yield ethyl2-[4-(2-{[(E)-amino(hydroxyimino)methyl][4-(2-cyclopropyl-1,3-oxazol-4-yl)benzyl]amino}ethyl)phenoxy]-2-methylpropanoate(0.46 g) which was used directly without purification.

¹H NMR (CDCl₃) δ 7.99 (s, 2H), 7.69 (s, 1 H), 7.58 (d, 2H, J=8.1), 7.14(d, 2H, J=8.1), 7.00 (d, 2H, J=8.5), 6.72 (d, 2H, J=8.5), 4.31 (s, 2H),4.18 (q, 2H, J=7.1), 3.40 (t, 2H, J=7.1), 2.73 (t, 2H, J=7.2), 2.08 (m,1H), 1.52 (s, 6H), 1.21 (t, 3H, J=7.3), 1.09-0.98 (m, 4H).

Step 5.

To a cooled solution of ethyl2-[4-(2-{[(E)-amino(hydroxyimino)methyl][4-(2-cyclopropyl-1,3-oxazo[4-yl)benzyl]amino}ethyl)phenoxy]-2-methylpropanoate(0.108 g, 0.21 mmol) in toluene (2 ml) was added triethylamine (0.028mL, 0.20 mmol) dropwise. After 5 min, 3-(trifluoromethyl)benzoylchloride (0.031 ml, 0.20 mmol) in toluene (0.1 ml) was added dropwise.The mixture was allowed to warm to rt over 2 h and then heated to 110Cfor 2 hr. upon cooling, the mixture was filtered, and the solid waswashed with EtOAc. The filtrate was concentrated in vacuo, and theresulting residue was partitioned between EtOAc and a solution of 0.5Naqueous HCl. The organic phase was washed with 0.5N aqueous HCl (1×),0.5N aqueous NaOH (2×), and brine (1×), dried with Na₂SO₄ andconcentrated in vacuo. The crude material was purified by flashchromatography (EtOAc/hexanes, 10:90 to 20:80) to yield ethyl2-{4-[2-([4-(2-cyclopropyl-1,3-oxazol-4-yl)benzyl]{5-[3-(trifluoromethyl)phenyl]-1,2,4-oxadiazol-3-yl}amino)ethyl]phenoxy}-2-methylpropanoate(76 mg, 58%).

¹H NMR (CDCl₃) δ 8.33 (s, 1H), 8.24 (d, 1H, J=8.0), 7.79 (d, 2H, J=8.0),7.69 (s, 1H), 7.62 (d, 2H, J=8.1), 7.24 (d, 2H, J=8.4), 7.02 (d, 2H,J=8.4), 6.74 (d, 2H, J 8.5), 4.55 (s, 2H), 4.20 (q, 2H, J=7.2), 3.54 (t,2H, J=7.2), 2.83 (t, 2H, J=7.8), 2.09 (m, 1H), 1.52 (s, 6H), 1.22 (t,3H, J=7.1), 1.10-1.01 (m, 4H).

Step 5.

To a solution of ethyl2-{4-[2-([4-(2-cyclopropyl-1,3-oxazo[4-yl)benzyl]{5-[3-(trifluoromethyl)phenyl]-1,2,4-oxadiazol-3-yl}amino)ethyl]phenoxy}-2-methylpropanoate(93 mg, 0.14 mmol) in anhydrous THF (1.5 ml) was added EtOH (0.4 ml),water (0.4 ml), and LiOH (31 mg, 1.28 mmol). The mixture was stirred atrt for 12 h. The reaction was quenched with a solution of saturatedaqueous KH₂PO₄, and the aqueous phase was extracted with EtOAc (3×20ml). The combined organic phases were dried with Na₂SO₄. andconcentrated in vacuo to yield the title compound as a colorless solid(58 mg, 65%). ¹H NMR (CDCl₃) δ 8.34 (s, 1H), 8.26 (d, 1H, J=7.9), 7.80(d, 1H, J=7.8), 7.65 (s, 1H), 7.62 (d, 1H, J=8.0), 7.40 (d, 2H, J=8.1),6.92 (d, 2H, J=8.3), 6.81 (d, 2H, J=8.5), 6.65 (d, 2H, J=8.4), 4.53 (s,2H), 3.63 (t, 2H, J=6.2), 2.92 (t, 2H, J=6.4), 2.21 (m, 1H), 1.58 (s,6H), 1.19-1.06 (m, 4H). MS: m/z 633 (M+1).

2-{4-[2-([4-(3-Cyclopropyl-5-isoxazolyl)benzyl]{5-[3-(trifluoromethyl)phenyl]-1,2,4-oxadiazol-3-yl}amino)ethyl]phenoxy}-2-methylpropanoicAcid

Similarly prepared from tyramine and4-(3-cyclopropyl-5-isoxazolyl)benzaldehyde.

¹H NMR (CDCl₃)δ 8.33 (s, 1H), 8.25 (d, 1H, J=8), 7.80 (d, 1H, J=7.9),7.65-7.61 (d+t, 3H), 7.20 (d, 2H, J=8.3), 6.98 (d, 2H, J=8.5), 6.76 (d,2H, J=8.6), 6.17 (s, 1H), 4.58 (s, 2H), 3.62 (t, 2H, J=6.9), 2.89 (t,2H, J=7.1), 2.05 (m, 1H), 1.53 (s, 6H), 1.10-1.00 (m, 4H).

2-{4-[2-([4-(4-Cyclopropyl-1,3-oxazol-2-yl)benzyl]{5-[3-(trifluoromethyl)phenyl]-1,2,4-oxadiazol-3-yl}amino)ethyl]phenoxy}-2-methylpropanoicAcid

Similarly prepared from tyramine and4-(4-cyclopropyl-1,3-oxazol-2-yl)benzaldehyde.

¹H NMR (CDCl₃) δ 8.34 (s, 1H), 8.26 (d, 1H, J=8.0), 7.81 (d, 1H, J=7.7),7.74 (d, 2H, J=8.1), 7.64 (t, 1H, J=7.7), 7.38 (s, 1H), 6.99 (d, 2H,J=8.3), 6.83 (d, 2H, J=8.2), 6.68 (d, 2H, J=8.6), 4.56 (s, 2H), 3.62 (t,2H, J=6.4), 2.92 (t, 2H, J=6.5), 1.87 (m, 1H), 1.58 (s, 6H), 0.93-0.80(m, 4H). MS: m/z 633 (M+1).

Ethyl2-[4-(2-{[(E)-amino(hydroxyimino)methyl][4-(trifluoromethyl)benzyl]amino}ethyl)phenoxy]-2-methylpropanoate

Step 1.

A solution of ethyl2-methyl-2-[4-(2-{[4-(trifluoromethyl)benzyl]amino}ethyl)phenoxy]propanoate(12 g; 29.34 mmol) and triethylamine (4.5 ml; 32.27 mmol) in 100 ml ofdichloromethane was treated under nitrogen with cyanogen bromide (10.3ml of a 3M solution in dichloromethane; 30.9 mmol). After 1.5 hr,additional triethylamine (2 ml) and cyanogen bromide (2.5 ml) were addedand stirred another 30 minutes. The reaction mixture was concentratedand the residue partitioned between ethyl acetate and water. The organicphase was washed with water (three times) and brine, dried over sodiumsulfate and concentrated. Purification by flash chromatography usingethyl acetate-hexane mixtures (5-40% gradient) afforded ethyl2-[4-(2-{cyano[4-(trifluoromethyl)benzyl]amino}ethyl)phenoxy]-2-methylpropanoate(10.9 g; 85% yield).

¹H NMR (CDCl₃) δ 7.6 (d, 2H, J=8.1), 7.31 (d, 2H, J=8.1), 7.04 (d, 2H,J=8.5), 6.79 (d, 2H, J=8.5), 4.24 (q, 2H, J=7.2), 4.14 (s, 2H), 3.14 (t,2H, J=7.4), 2.89 (t, 2H, J=7.4), 1.58 (s, 6H), 1.25 (t, 3H, J=7.2).

Step 2.

A solution of the above intermediate (10.9 g; 25.28 mmol) in 80 ml ofdry DMF was treated under nitrogen with hydroxylamine hydrochloride(6.32 g; 90.99 mmol) and sodium acetate (7.46 g; 90.99 mmol). After 14hr, the reaction mixture was partitioned between ethyl acetate and 0.05NNaOH. The organic phase was washed with water (twice) and brine, driedover sodium sulfate and concentrated. Purification by flashchromatography using methanol-dichloromethane mixtures (2-20% gradient)afforded the title compound in good yield (˜85% purity).

¹H NMR (CDCl₃) δ 7.58 (d, 2H, J=8.1), 7.35 (d, 2H, J=8.1), 7.05 (d, 2H,J=8.5), 6.8 (d, 2H, J=8.5), 4.4 (s, 2H), 4.28 (q, 2H, J=7.2), 3.39 (t,2H, J=7.3), 2.80,t, 2H, J=7.3), 1.59 (s, 6H), 1.28 (t, 3H, J=7.2).

tert-Butyl2-[4-(2-{[(E)-amino(hydroxyimino)methyl][4-(trifluoromethyl)benzyl]amino}ethyl)phenoxy]-2-methylpropanoate

Similarly prepared from tert-butyl2-methyl-2-[4-(2-{[4-(trifluoromethyl)benzyl]amino}ethyl)phenoxy]propanoate.

¹H NMR (CDCl₃) δ 7.55 (d, 2H, J=8), 7.32 (d, 2H, J=8), 7.01 (d, 2H,J=8.5), 6.78 (d, 2H. J=8.5), 4.34 (s, 2H), 3.32 (t, 2H, J=7.4), 2.80 (t,2H, J=7.4), 1.53 (s, 6H), 1.43 (s, 9H).

2-[4-(2-{(5-Isopropyl-1,2,4-oxadiazol-3-yl)[4-(trifluoromethyl)benzyl]amino}ethyl)phenoxy]-2-methylpropanoicAcid

Step 1.

A solution of ethyl2-[4-(2-{[(E)-amino(hydroxyimino)methyl][4-(trifluoromethyl)benzyl]amino}ethyl)phenoxy]-2-methylpropanoate(1 g; 2.14 mmol) and triethylamine (0.30 ml; 2.14 mmol) in 10 ml ofdichloromethane was cooled in an ice bath and treated under nitrogenwith isobutyryl chloride (0.20 ml; 1.93 mmol). The mixture was allowedto warm to rt. After 1 hr, 8 ml of toluene were added and the reactionmixture was heated to 110C under a reflux condenser. After 5 hr, it waspartitioned between ethyl acetate and 0.5N HCl. The organic phase waswashed with 0.5 N HCl (twice), 1 N NaOH (three times) and brine, driedover sodium sulfate and concentrated. Purification by flashchromatography using ethyl acetate-hexane mixtures (5-50% gradient)afforded ethyl2-[4-(2-{(5-isopropyl-1,2,4-oxadiazol-3-yl)[4-(trifluoromethyl)benzyl]amino}ethyl)phenoxy]-2-methylpropanoate(470 mg; 43% yield).

Step 2.

The intermediate ester above (1 g) was hydrolyzed with NaOH as pergeneral procedure H. Purification by radial chromatography using a 1-8%methanol-dichloromethane gradient, followed by crystallization fromdichloromethane-hexane afforded the title compound as a white solid(0.80 g; 85% yield).

¹H NMR (CDCl₃) δ 7.52 (d, 2H, J=8.1), 7.29 (d, 2H, J=8.1), 7.01 (d, 2H,J=8.5), 6.81 (d, 2H, J=8.5), 4.5 (s, 2H), 3.49 (t, 2H, J=7.5), 3.06 (m,1H), 2.80 (t, 2H, J=7.5), 1.54 (s, 6H), 1.33 (d, 6H, J=7.1).

2-[4-(2-{[5-(3-Chlorophenyl)-1,2,4-oxadiazol-3-yl][4-(trifluoromethyl)benzyl]amino}ethyl)phenoxy]-2-methylpropanoicAcid

Similarly prepared from ethyl2-[4-(2-{[(E)-amino(hydroxyimino)methyl][4-(trifluoromethyl)benzyl]amino}ethyl)phenoxy]-2-methylpropanoateand 3 chlorobenzoyl chloride.

¹H NMR (CDCl₃) δ 8.03 (s, 1 H), 7.92 (d, 1H, J=7.8), 7.54 (d, 2H,J=8.2), 7.51 (d, 1H, J=7.8), 7.41 (t, 1H, J=7.8), 7.32 (d, 2H, J=8.2),7.06 (d, 2H, J=8.4), 6.84 (d, 2H, J=8.4), 4.57 (s, 2H), 3.58 (t, 2H,J=7.6), 2.87 (t, 2H, J=7.6), 1.55 (s, 6H).

2-Methyl-2-{4-[2-([4-(trifluoromethyl)benzyl]{5-[4-(trifluoromethyl)phenyl]-1,2,4-oxadiazol-3-yl}amino)ethyl]phenoxy}propanoicAcid

Similarly prepared by condensation of tert-butyl2-[4-(2-{[(E)-amino(hydroxyimino)methyl][4-(trifluoromethyl)benzyl]amino}ethyl)phenoxy]-2-methylpropanoatewith 4-trifluoromethylbenzoyl chloride, followed by standard TFAhydrolysis.

¹H NMR (CDCl₃) δ 8.23 (d, 2H, J=8.1), 7.8 (d, 2H, J=8.1), 7.6 (d, 2H,J=8.1), 7.39 (d, 2H, J=8.1), 7.13 (d, 2H, J=8.5), 6.9 (d, 2H, J=8.5),4.65 (s, 2H), 3.66 (t, 2H, J=7.7), 2.94 (t, 2H, J=7.7), 1.6 (s, 6H).

2-[4-(2-{(5-Cyclohexyl-1,2,4-oxadiazol-3-yl)[4-(trifluoromethyl)benzyl]amino}ethyl)phenoxy]-2-methylpropanoicAcid

Similarly prepared from tert-butyl2-[4-(2-{[(E)-amino(hydroxyimino)methyl][4-(trifluoromethyl)benzyl]amino}ethyl)phenoxy]-2-methylpropanoateand cyclohexanecarbonyl chloride.

¹H NMR (CDCl₃) δ 7.58 (d, 2H, J=8.1), 7.35 (d, 2H, J=8.1), 7.09 (d, 2H,J=8.5), 6.88 (d, 2H, J=8.5), 4.56 (s, 2H), 3.55 (t, 2H, J=7.4), 2.85 (m,3H), 2.09 (m, 2H), 1.85 (m, 2H), 1.65 (m, 2H), 1.6 (s, 6H), 1.38 (m,4H).

The following 62 compounds were prepared using similar procedures tothose described above.

2-methyl-2-[4-(2-{(5-pyridin-4-yl-1,2,4-oxadiazol-3-yl)[4-(trifluoromethyl)benzyl]amino}ethyl)phenoxy]propanoicAcid

MS: m/z 527.0 (M+1)

2-[4-(2-{[5-(4-cyanophenyl)-1,2,4-oxadiazol-3-yl][4-(trifluoromethyl)benzyl]amino}ethyl)phenoxy]-2-methylpropanoicAcid

MS: m/z 551 (M+1)

2-[4-(2-{(5-cyclopropyl-1,2,4-oxadiazol-3-yl)[4-(trifluoromethyl)benzyl]amino}ethyl)phenoxy]-2-methylpropanoicAcid

MS: m/z 490.1 (M+1)

2-[4-(2-{(5-tert-butyl-1,2,4-oxadiazol-3-yl)[4-(trifluoromethyl)benzyl]amino}ethyl)phenoxy]-2-methylpropanoicAcid

MS: m/z 506.2 (M+1)

2-[4-(2-{(5-cyclobutyl-1,2,4oxadiazol-3-yl)[4-(trifluoromethyl)benzyl]amino}ethyl)phenoxy]-2-methylpropanoicAcid

MS: m/z 504.3 (M+1)

2-[4-(2-{(5-cyclopentyl-1,2,4-oxadiazol-3-yl)[4-(trifluoromethyl)benzyl]amino}ethyl)phenoxy]-2-methylpropanoicAcid

MS: m/z 518.3 (M+1)

2-[4-(2-{(5-isobutyl-1,2,4-oxadiazol-3-yl)[4-(trifluoromethyl)benzyl]amino}ethyl)phenoxy]-2-methylpropanoicAcid

MS: m/z 506.3 (M+1)

2-methyl-2-[4-(2-{(5-thien-2-yl-1,2,4-oxadiazol-3-yl)[4-(trifluoromethyl)benzyl]amino}ethyl)phenoxylpropanoicAcid

MS: m/z 532.2 (M+1)

2-methyl-2-[4-(2-{(5-phenyl-1,2,4-oxadiazol-3-yl)[4-(trifluoromethyl)benzyl]amino}ethyl)phenoxy]propanoicAcid

MS: m/z 526.2 (M+1)

2-[4-(2-{[5-(3,4-dichlorophenyl)-1,2,4-oxadiazol-3-yl][4-(trifluoromethyl)benzyl]amino}ethyl)phenoxy]-2-methylpropanoicAcid

MS: m/z 594 (M+1)

2-[4-(2-{(5-cycloheptyl-1,2,4-oxadiazol-3-yl)[4-(trifluoromethyl)benzyl]amino}ethyl)phenoxy]-2-methylpropanoicAcid

MS: m/z 544 (M−1)

2-methyl-2-[4-(2-{(5-thien-3-yl-1,2,4-oxadiazol-3-yl)[4-(trifluoromethyl)benzyl]amino}ethyl)phenoxy]propanoicAcid

MS: m/z 529.8 (M−1)

2-methyl-2-[4-(2-{[5-(phenoxymethyl)-1,2,4-oxadiazol-3-yl][4-(trifluoromethyl)benzyl]amino}ethyl)phenoxy]propanoicAcid

MS: m/z 556.1 (M+1)

2-methyl-2-[4-(2-{[5-(4-methylphenyl)-1,2,4-oxadiazol-3-yl][4-(trifluoromethyl)benzyl]amino}ethyl)phenoxy]propanoicAcid

MS: m/z 540.1 (M+1)

2-methyl-2-[4-(2-{[5-(3-methylphenyl)-1,2,4-oxadiazol-3-yl][4-(trifluoromethyl)benzyl]amino}ethyl)phenoxy]propanoicAcid

MS: m/z 540.1 (M+1)

2-[4-(2-{(5-isopentyl-1,2,4-oxadiazol-3-yl)[4-(trifluoromethyl)benzyl]amino}ethyl)phenoxy]-2-methylpropanoicAcid

MS: m/z 520.2 (M+1)

2-[4-(2-{[5-(cyclopentylmethyl)-1,2,4-oxadiazol-3-yl][4-(trifluoromethyl)benzyl]amino}ethyl)phenoxy]-2-methylpropanoicAcid

MS: m/z 532.2 (M+1)

2-methyl-2-[4-(2-{(5-propyl-1,2,4-oxadiazol-3-yl][4-(trifluoromethyl)benzyl]amino}ethyl)phenoxy]propanoicAcid

MS: m/z 492.1 (M+1)

2-methyl-2-[4-(2-{[5-(2-methylphenyl)-1,2,4-oxadiazol-3-yl][4-(trifluoromethyl)benzyl]amino}ethyl)phenoxy]propanoicAcid

2-methyl-2-[4-(2-{[4-(trifluoromethyl)benzyl][5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]amino}ethyl)phenoxy]propanoicAcid

MS: m/z 518.1 (M+1)

2-methyl-2-[4-(2-{[4-(trifluoromethyl)benzyl][5-(3,3,3-trifluoropropyl)-1,2,4-oxadiazol-3-yl]amino}ethyl)phenoxy]propanoicAcid

MS: m/z 546.1 (M+1)

2-methyl-2-[4-(2-{5-tetrahydrofuran-3-yl-1,2,4-oxadiazol-3-yl)[4-(trifluoromethyl)benzyl]amino}ethyl)phenoxy]propanoicAcid

MS: m/z 520.1 (M+1)

2-(4-{2-[[2,4-bis(trifluoromethyl)benzyl](5-isopropyl-1,2,4-oxadiazol-3-yl)amino]ethyl}phenoxy)-2-methylpropanoicAcid

2-{4-[2-([2,4-bis(trifluoromethyl)benzyl]{5-[4-(trifluoromethyl)phenyl]-1,2,4-oxadiazol-3-yl}amino)ethyl]phenoxy}-2-methylpropanoicAcid

MS: m/z 661.8 (M+1)

2-methyl-2-{4-[2-([4-(trifluoromethoxy)benzyl]{5-[4-(trifluoromethoxy)phenyl]-1,2,4-oxadiazol-3-yl}amino)ethyl]phenoxy)propanoicAcid

2-methyl-2-{4-[2-([4-trifluoromethoxy)benzyl]{5-[3-(trifluoromethyl)phenyl]-1,2,4-oxadiazol-3-yl}amino)ethyl]phenoxy}propanoicAcid

2-methyl-2-{4-[2-([4-(trifluoromethoxy)benzyl]{5-[4-(trifluoromethyl)phenyl]-1,2,4-oxadiazol-3-yl}amino)ethyl]phenoxy}propanoicAcid

2-(4-(2-(4-isopropyl-1,2,4-oxadiazol-3-yl)[4-(trifluoromethoxy)benzyl]amino}ethyl)phenoxy]-2-methylpropanoicAcid

2-{4-[2-((5-isopropyl-1,2,4-oxadiazol-3-yl){4-[(trifluoromethyl)thio]benzyl}amino)ethyl]phenoxy}-2-methylpropanoicAcid

2-[4-(2-{(5-isopropyl-1,2,4-oxadiazol-3-yl)[4-(methylthio)benzyl]amino}ethyl)phenoxy]-2-methylpropanoicAcid

2-[4-(2-{{5-[1-(tert-butoxycarbonyl)piperidin-4-yl]-1,2,4-oxadiazol-3-yl}[4-(trifluoromethyl)benzyl]amino}ethyl)phenoxy]-2-methylpropanoicAcid

MS: m/z 633.2 (M+1)

2-[4-(2-{[5-(1-acetylpiperidin-4-yl)-1,2,4-oxadiazol-3-yl[]4-(trifluoromethyl)benzyl]amino}ethyl)phenoxy]-2-methylpropanoicAcid

MS: m/z 515.1 (M+1)

2-methyl-2-[4-(2-{(5-{1-[(methylamino)carbonyl]piperidin-4-yl}-1,2,4-oxadiazol-3-yl)[4-(trifluoromethyl)benzyl]amino}ethyl)phenoxy]propanoicAcid

MS: m/z 590.1 (M+1)

2-[4-(2-{[5-(1-benzylpiperidin-4-yl)-1,2,4-oxadiazol-3-yl][4-(trifluoromethyl)benzyl]amino}ethyl)phenoxy]-2-methylpropanoicAcid

MS: m/z 623.2 (M+1)

2-[4-(2-{{5-[1-(methoxycarbonyl)piperidin-4-yl]-1,2,4-oxadiazol-3-yl}[4-(trifluoromethyl)benzyl]amino}ethyl)phenoxy]-2-methylpropanoicAcid

MS: m/z 591.2 (M+1)

2-[4-(2-{[5-(1-ethylpiperidin-4-yl)-1,2,4-oxadiazol-3-yl][4-(trifluoromethyl)benzyl]amino}ethyl)phenoxy]-2-methylpropanoicAcid MS: m/z 561.1 (M+1)

2-[4-(2-{{5-[1-(aminocarbonyl)piperidine-4-yl]-1,2,4-oxadiazol-3-yl}[4-(trifluoromethyl)benzyl]amino}ethyl)phenoxy]-2-methylpropanoicAcid

MS: m/z 576.2 (M+1)

2-[4-(2-{{5-[1-(isobutoxycarbonyl)piperidin-4-yl]-1,2,4-oxadiazol-3-yl}[4-(trifluoromethyl)benzyl]amino}ethyl)phenoxy]-2-methylpropanoicAcid

MS: m/z 633 (M+1)

2-[4-(2-{{5-[1-(ethoxycarbonyl)piperidin-4-yl-1,2,4-oxadiazol-3-yl}[4-(trifluoromethyl)benzyl]amino}ethyl)phenoxy]-2-methylpropanoicAcid

MS: m/z 605 (M+1)

2-methyl-2-[4-(2-{{5-[1-(methylsulfonyl)piperidin-4-yl]-1,2,4-oxadiazol-3-yl}[4-(trifluoromethyl)benzyl]amino}ethyl)phenoxy]propanoicAcid

2-[4-(2-{(5-{1-[(benzyloxy)carbonyl]piperidin-4-yl-1,2,4-oxadiazol-3-yl)[4-(trifluoromethyl)benzyl]amino}ethyl)phenoxy]-2-methylpropanoicAcid

MS: m/z 667 (M+1)

2-[4-(2-{(5-{[4-(4-fluorophenyl)piperazin-1-yl]methyl}-1,2,4-oxadiazol-3-yl)[4-(trifluoromethyl)benzyl]amino}ethyl)phenoxy]-2-methylpropanoicAcid

MS: m/z 640.1 (M−1)

2-methyl-2-[4-(2-{[5-(morpholin-4-ylmethyl}-1,2,4-oxadiazol-3-yl][4-(trifluoromethyl)benzyl]amino}ethyl)phenoxy]propanoicAcid

MS: m/z 549 (M+1)

2-[4-(2-{(5-isopropyl-1,2,4-oxadiazol-3-yl)[4-(trifluoromethyl)benzyl]amino}-1,1-dimethylethyl)phenoxy]-2-methylpropanoicAcid

2-methyl-2-{2-methyl-4-[2-([4-(trifluoromethoxy)benzyl]{5-[4-(trifluoromethyl)phenyl]-1,2,4-oxadiazol-3-yl}amino)ethyl]phenoxy}propanoicAcid

2-methyl-2-{4-[2-(methyl{5-[3-(trifluoromethyl)phenyl]-1,2,4-oxadiazol-3-yl}amino)ethyl]phenoxy}propanoicAcid

MS: m/z 506.2 (M+1)

2-methyl-2-[3-(3-{[5-(2-methylphenyl)-1,2,4-oxadiazol-3-yl][4-(trifluoromethyl)benzyl]amino}propyl)phenoxy]propanoicAcid

2-methyl-2-[3-(3-{[5-(3-methylphenyl)-1,2,4-oxadiazol-3-yl][4-(trifluoromethyl)benzyl]amino}propyl)phenoxy]propanoicAcid

2-methyl-2-[3-(3-{[5-(4-methylphenyl)-1,2,4-oxadiazol-3-yl][4-(trifluoromethyl)benzyl]amino}propyl)phenoxy]propanoicAcid

2-[3-(3-{5-(4-cyanophenyl)-1,2,4-oxadiazol-3-yl][4-(trifluoromethyl)benzyl]amino}propyl)phenoxy]-2-methylpropanoicAcid

2-[3-(3-{[5-(3-cyanophenyl)-1,2,4-oxadiazol-3-yl][4-(trifluoromethyl)benzyl]amino}propyl)phenoxy]-2-methylpropanoicAcid

2-[3-(3-{(5-cyclopropyl-1,2,4-oxadiazol-3-yl)[4-(trifluoromethyl)benzyl]amino}propyl)phenoxy]-2-methylpropanoicAcid

2-[3-(3-{(5-cyclobutyl-1,2,4-oxadiazol-3-yl)[4-(trifluoromethyl)benzyl]amino}propyl)phenoxy]-2-methylpropanoicAcid

2-[3-(3-{(5-cyclopentyl-1,2,4-oxadiazol-3-yl)[4-(trifluoromethyl)benzyl]amino}propyl)phenoxy]-2-methylpropanoicAcid

2-[3-(3-{[5-(cyclopentylmethyl)-1,2,4-oxadiazol-3-yl][4-(trifluoromethyl)benzyl]amino}propyl)phenoxy]-2-methylpropanoicAcid

2-methyl-2-[3-(3-{(5-methyl-1,2,4-oxadiazol-3-yl)[4-(trifluoromethyl)benzyl]amino}propyl)phenoxy]propanoicAcid

2-methyl-2-[3-(3-{(5propyl-1,2,4-oxadiazol-3-yl)[4-(trifluoromethyl)benzyl]amino}propyl)phenoxy]propanoicAcid

2-[3-(3-{(5-butyl-1,2,4-oxadiazol-3-yl)[4-(trifluoromethyl)benzyl]amino}propyl)phenoxy]-2-methylpropanoicAcid

2-[3-(3-{(5-isopropyl-1,2,4-oxadiazol-3-yl)[4-(trifluoromethyl)benzyl]amino}propyl)phenoxy]-2-methylpropanoicAcid

2-[3-(3-{(5-isobutyl-1,2,4-oxadiazol-3-yl)[4-(trifluoromethyl)benzyl]amino}propyl)phenoxy]-2-methylpropanoicAcid

2-[3-(3-{(5-tert-butyl-1,2,4-oxadiazol-3-yl)[4-(trifluoromethyl)benzyl]amino}propyl)phenoxy]-2-methylpropanoicAcid

2-[3-(3-{[5-(2-furyl)-1,2,4-oxadiazol-3-yl][4-(trifluoromethyl)benzyl]amino}propyl)phenoxy]-2-methylpropanoicAcid

2-{4-[2-([4-(5-Cyclopropyl-1,2,4-oxadiazol-3-yl)benzyl]{5-[4-(trifluoromethyl)phenyl]-1,2,4-oxadiazol-3-yl}amino)ethyl]phenoxy}-2-methylpropanoicAcid

Similarly prepared from tert-butyl2-[4-(2-{[4-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)benzyl]amino}ethyl)phenoxy]-2-methylpropanoateand 4-trifluoromethyl benzoyl chloride.

¹H NMR (CDCl₃) δ 8.21 (d, 2H, J=8.2), 7.9 (d, 2H, J=8.2), 7.7 (d, 2H,J=8.2), 7.22 (d, 2H, J=8.2), 6.99 (d, 2H, J=8.5), 6.78 (d, 2H, J=8.5),4.61 (s, 2H), 3.64 (t, 2H, J=7.2), 2.92 (t, 2H, J=7.2), 2.28 (m, 1H),1.57 (s, 6H), 1.30 (m, 4H).

2-[4-(2-{[4-(5-Cyclopropyl-1,2,4-oxadiazol-3-yl)benzyl][5-(4-fluorophenyl)-1,2,4-oxadiazol-3-yl]amino}ethyl)phenoxy]-2-methylpropanoicAcid

Similarly prepared from tert-butyl2-[4-(2-{[4-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)benzyl]amino}ethyl)phenoxy]-2-methylpropanoateand 4-fluorobenzoyl chloride.

¹H NMR (CDCl₃) δ 8.13 (m, 2H), 7.94 (d, 2H, J=8.2), 7.26 (m, 4H), 7.04(d, 2H, J=8.5), 6.83 (d, 2H, J=8.5), 4.63 (s, 2H), 3.65 (t, 2H, J=7.4),2.94 (t, 2H, J=7.4), 2.31 (m, 1H), 1.61 (s, 6H), 1.32 (m, 4H).

2-[4-(2-{(5-Cyclohexyl-1,2,4-oxadiazol-3-yl)[4-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)benzyl]amino}ethyl)phenoxy]-2-methylpropanoicAcid

Similarly prepared from tert-butyl2-[4-(2-{[4-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)benzyl]amino}ethyl)phenoxy]-2-methylpropanoateand cyclohexanecarbonyl chloride. ¹H NMR (CDCl₃) δ 7.87 (d, 2H, J=8.3),7.17 (d, 2H, J=8.3), 6.95 (d, 2H, J=8.5), 6.76 (d, 2H, J=8.5), 4.52 (s,2H), 3.53 (t, 2H, J=7.2), 2.83 (m, 3H), 2.28 (m, 1H), 2.06 (m, 2H), 1.83(m, 2H), 1.65 (m, 2H), 1.57 (s, 6H), 1.32 (m, 8H).

The following 22 compounds were prepared using similar procedures tothose described above.

2-(4-{2-[[4-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)benzyl](5-methyl-1,2,4-oxadiazol-3-yl)amino]ethyl}phenoxy)-2-methylpropanoicAcid

MS: m/z 504.3 (M+1).

2-[4-(2-{(5-cyclopropyl-1,2,4-oxadiazol-3-yl)[4-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)benzyl]amino}ethyl)phenoxy]-2-methylpropanoicAcid

MS: m/z 530.3 (M+1)

2-(4-{2-[[4-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)benzyl](5-thien-2-yl-1,2,4-oxadiazol-3-yl)amino]ethyl}phenoxy)-2-methylpropanoicAcid

MS: m/z 572.2 (M+1)

2-(4-{2-[[4-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)benzyl](1,2,4-oxadiazol-3-yl)amino]ethyl}phenoxy)-2-methylpropanoicAcid

MS: m/z 490.2 (M+1)

2-[4-(2-{(5-butyl-1,2,4-oxadiazol-3-yl)[4-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)benzyl]amino}ethyl)phenoxy]-2-methylpropanoicAcid

MS: m/z 546.3 (M+1)

2-(4-{2-[[4-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)benzyl](5-isobutyl-1,2,4-oxadiazol-3-yl)amino]ethyl}phenoxy)-2-methylpropanoicAcid

MS: m/z 546.3 (M+1)

2-(4-{2-[[4-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)benzyl](5-isopentyl-1,2,4-oxadiazol-3-yl)amino]ethyl}phenoxy)-2-methylpropanoicAcid

MS: m/z 560.3 (M+1)

2-[4-(2-{[5-(cyclopentylmethyl)-1,2,4-oxadiazol-3-yl][4-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)benzyl]amino}ethyl)phenoxy]-2-methylpropanoicAcid

MS: m/z 572.3 (M+1)

2-(4-{2-[[4-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)benzyl](5-phenyl-1,2,4-oxadiazol-3-yl)amino]ethyl{phenoxy)-2-methylpropanoicAcid

MS: m/z 566.2 (M+1)

2-[4-(2-{[5-(4-chlorophenyl)-1,2,4-oxadiazol-3-yl][4-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)benzyl]amino}ethyl)phenoxy]-2-methylpropanoicAcid MS: m/z 600.2 (M+1)

2-[4-(2-{[5-(3-chlorophenyl)-1,2,4-oxadiazol-3-yl][4-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)benzyl]amino}ethyl)phenoxy]-2-methylpropanoicAcid

MS: m/z 600.2 (M+1)

2-[4-(2-{[4-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)benzyl][5-(2-fluorophenyl)-1,2,4-oxadiazol-3-yl]amino}ethyl)phenoxy]-2-methylpropanoicAcid MS: m/z 584.3 (M+1)

2-[4-(2-{[4-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)benzyl][5-(2-methylphenyl)-1,2,4-oxadiazol-3-yl]amino}ethyl)phenoxy]-2-methylpropanoicAcid MS: m/z 580.3 (M+1)

2-{4-[2-([4-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)benzyl]{5-[3-(trifluoromethyl)phenyl]-1,2,4-oxadiazol-3-yl}amino)ethyl]phenoxy}-2-methylpropanoicAcid

MS: m/z 633.9 (M+1)

2-[4-(2-[4-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)benzyl][5-(4-methylphenyl)-1,2,4-oxadiazol-3-yl]amino}ethyl)phenoxy]-2-methylpropanoicAcid

MS: m/z 577.6 (M-1)

2-[4-(2-{[4-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)benzyl][5-(3,4-dichlorophenyl)-1,2,4-oxadiazol-3-yl]amino}ethyl)phenoxy]-2-methylpropanoicAcid

MS: m/z 634.1 (M+1)

2-(4-{2-[[4-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)benzyl](5-pyridin-2-yl-1,2,4-oxadiazol-3-yl)amino]ethyl}phenoxy)-2-methylpropanoicAcid

MS: m/z 567.2 (M+1)

2-{4-[2-([4-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)benzyl]{5-[3-fluoro-4-(trifluoromethyl)phenyl]-1,2,4-oxadiazol-3-yl}amino)ethyl]phenoxy}-2-methylpropanoicAcid

MS: m/z 649.7 (M−1)

2-[4-(2-{[4-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)benzyl][5-(3-methylphenyl)-1,2,4-oxadiazol-3-yl]amino}ethyl)phenoxy]-2-methylpropanoicAcid

MS: m/z 580.2 (M+1)

2-[4-(2-{(5-cyclopentyl-1,2,4-oxadiazol-3-yl)[4-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)benzyl]amino}ethyl)phenoxy]-2-methylpropanoicAcid

MS: m/z 556.1 (M−1)

2-[4-(2-{[5-(4-chlorophenyl)-1,2,4-oxadiazol-3-yl][4-(5-isopropyl-1,2,4-oxadiazol-3-yl)benzyl]amino}ethyl)phenoxy]-2-methylpropanoicAcid

MS: m/z 602.1 (M+1)

2-{4-[2-([4-(5-isopropyl-1,2,4-oxadiazol-3-yl)benzyl]{5-[4-(trifluoromethyl)phenyl]-1,2,4-oxadiazol-3-yl}amino)ethyl]phenoxy}-2-methylpropanoicAcid

MS: m/z 636.1 (M+1)

Ethyl2-[4-(2-{(aminocarbonothioyl)[4-(trifluoromethyl)benzyl]amino}ethyl)phenoxy]-2-methylpropanoate

A solution of ethyl2-methyl-2-[4-(2-([4-(trifluoromethyl)benzyl]amino}ethyl)phenoxy]propanoate(9 g; 22 mmol) and ammonium thiocyanate (1.67 g; 22 mmol) in 44 ml ofxylene was heated at reflux for 12 hr. The mixture was concentrated andpurified by flash chromatography using ethyl acetate-hexane mixtures(20-40% gradient) to afford the title compound (6.4 g; 62% yield).

¹H NMR (CDCl₃) δ 7.57 (d, 2H, J=7.9), 7.32 (d, 2H, J=7.6), 7.01 (d, 2H,J=8.), 6.78 (d, 2H, J=8.5), 4.20 (q, 2H, J=7.0), 3.73 (b, 2H), 2.89 (b,2H), 1.54 (s, 6H), 1.23 (t, 3H, J=7.3).

Ethyl2-[4-(2-{(aminocarbonothioyl)[2,4-bis(trifluoromethyl)benzyl]amino}ethyl)phenoxy]-2-methylpropanoate

Similarly prepared from ethyl2-[4-(2-{[2,4-bis(trifluoromethyl)benzyl]amino}ethyl)phenoxy]-2-methylpropanoate.

¹H NMR (CDCl₃) δ 7.85 (s, 1H), 7.71 (d, 1H, J=7.7), 7.53 (b, 2H), 7.00(d, 2H, J=7.9), 6.74 (d, 2H, J=8.1), 4.17 (q, 2H, J=6.9), 3.58 (b, 2H),2.87 (b, 2H), 1.51 (s, 6H), 1.20(t, 3H, J=7.0).

2-[4-(2-{[4-(3-Chlorophenyl)-1,3-thiazol-2-yl][4-(trifluoromethyl)benzyl]amino}ethyl)phenoxy]-2-methylpropanoicAcid

Step 1.

A solution of ethyl2-[4-(2-{(aminocarbonothioyl)[4-(trifluoromethyl)benzyl]amino}ethyl)phenoxy]-2-methylpropanoate(162 mg; 0.35 mmol) and 3-chlorophenacyl bromide (82 mg; 0.35 mmol) inEtOH (4 ml) was heated to reflux for 12 hr. Upon cooling the mixture wasconcentrated and the residue purified by flash chromatography usingethyl acetate-hexane mixtures (5-50% gradient) to afford ethyl2-[4-(2-{[4-(3-chlorophenyl)-1,3-thiazol-2-yl][4-(trifluoromethyl)benzyl]amino}ethyl)phenoxy]-2-methylpropanoate(128 mg; 61% yield).

Step 2.

The intermediate ester above was hydrolyzed with LiOH as per generalprocedure H. After standard aqueous workup the title compound wasobtained in good yield.

¹H NMR (CD₃OD) δ 7.84 (s, 1H), 7.74 (d, 1H, J=7.7), 7.63 (d, 2H, J=8.1),7.47 (d, 2H, J=8.0), 7.36-7.24 (m, 3H), 7.13 (d, 2H, J=8.2), 7.00 (s,1H), 6.85 (d, 2H, J=8.4), 4.73 (s, 1H), 3.72 (t, 2H, J=7.2), 2.96 (t,2H, J=7.4), 1.52 (s, 6H). MS: m/z 575 (M+1).

2-Methyl-2-[4-(2-{[4-(trifluoromethyl)benzyl][4-(trifluoromethyl)-1,3-thiazol-2-yl]amino}ethyl)phenoxy]propanoicAcid

Similarly prepared from ethyl2-[4-(2-{(aminocarbonothioyl)[4-(trifluoromethyl)benzyl]amino}ethyl)phenoxy]-2-methylpropanoateand 3-bromo-1,1,1-trifluoroacetone.

¹H NMR (CD₃OD) δ 7.62 (d, 2H, J=8.1), 7.42 (d, 2H, J=8.0), 7.15 (s, 1H),7.09 (d, 2H, J=8.4), 6.83 (d, 2H, J=8.4), 4.68 (s, 2H), 3.68 (t, 2H,J=7.2), 2.91 (t, 2H, J=7.3), 1.52 (s, 6H). MS: m/z 533 (M+1).

2-[4-(2-{[4-(2-Chlorophenyl)-1,3-thiazol-2-yl][4-(trifluoromethyl)benzyl]amino}ethyl)phenoxy]-2-methylpropanoicAcid

Similarly prepared from ethyl2-[4-(2-{(aminocarbonothioyl)[4-(trifluoromethyl)benzyl]amino}ethyl)phenoxy]-2-methylpropanoateand 2-chlorophenacyl bromide.

¹H NMR (CD₃OD) δ 7.80 (d, 1H, J=7.5), 7.60 (d, 1H, J=8.0), 7.46-7.42 (m,3H), 7.39-7.23 (m, 2H), 7.10 (d, 2H, J=8.4), 7.03 (s, 1H), 6.84 (d, 2H,J=8.3), 4.69 (s, 2H), 3.69 (t, 2H, J=7.0), 2.95 (t, 2H, J=7.1), 1.52 (s,6H). MS: m/z 575 (M+1).

2-[4-(2-{[4-(3,4-Difluorophenyl)-1,3-thiazol-2-yl][4-(trifluoromethyl)benzyl]amino}ethyl)phenoxy]-2-methylpropanoicAcid

Similarly prepared from ethyl2-[4-(2-{(aminocarbonothioyl)[4-(trifluoromethyl)benzyl]amino}ethyl)phenoxy]-2-methylpropanoateand 3,4-difluorophenacyl bromide.

¹H NMR (CD₃OD) δ 7.74-7.67 (m, 1H), 7.62 (d, 2H, J=8.1), 7.46 (d, 2H,J=8.0), 7.37-7.18 (m, 2H), 7.12 (d, 2H, J=8.4), 6.95 (s, 1H), 6.84 (d,2H, J=8.4), 4.72 (s, 2H), 3.71 (t, 2H, J=7.2), 3.34 (t, 2H, J=7.2), 1.52(s, 6H). MS: m/z 577 (M+1).

2-[4-(2-{[4-(2-Methoxyphenyl)-1,3-thiazol-2-yl][4-(trifluoromethyl)benzyl]amino}ethyl)phenoxy]-2-methylpropanoicAcid

Similarly prepared from ethyl2-[4-(2-{(aminocarbonothioyl)[4-(trifluoromethyl)benzyl]amino}ethyl)phenoxy]-2-methylpropanoateand 2-methoxyphenacyl bromide.

¹H NMR (CD₃OD) δ 8.07 (d, 1H, J=7.8), 7.62 (d, 2H, J=8.0), 7.47 (d, 2H,J=8.0), 7.24 (t, 1H, J=7.4), 7.12 (d, 2H, J=8.4), 7.02-6.95 (m, 3H),6.85 (d, 2H, J=8.4), 4.72 (s, 2H), 3.92 (s, 3H), 3.70 (t, 2H, J=7.1),2.96 (t, 2H, J=7.1), 1.52 (s, 6H). MS: m/z 571 (M+1).

2-[4-(2-{[4-(3-methoxyphenyl)-1,3-thiazol-2-yl][4-(trifluoromethyl)benzyl]amino}ethyl)phenoxy]-2-methylpropanoicAcid

Similarly prepared from ethyl2-[4-(2-{(aminocarbonothioyl)[4-(trifluoromethyl)benzyl]amino}ethyl)phenoxy]-2-methylpropanoateand 3-methoxyphenacyl bromide.

¹H NMR (CD₃OD) δ 7.63 (d, 2H, J=8.2), 7.48 (d, 2H, J=8.1), 7.43-7.40 (m,2H), 7.28 (t, 1H, J=8.2), 7.15 (d, 2H, J=8.3), 6.86 (m, 3H), 4.74 (s,2H), 3.83 (s, 3H), 3.73 (t, 2H, J=7.3), 2.97 (t, 2H, J=7.4), 1.55 (s,6H). MS: m/z 571 (M+1).

2-[4-(2-{[4-(4-Chlorophenyl)-1,3-thiazol-2-yl][4-(trifluoromethyl)benzyl]amino}ethyl)phenoxy]-2-methylpropanoicAcid

Similarly prepared from ethyl2-[4-(2-{(aminocarbonothioyl)[4-(trifluoromethyl)benzyl]amino}ethyl)phenoxy]-2-methylpropanoateand 4-chlorophenacyl bromide.

¹H NMR (CD₃OD) δ 7.80 (d, 2H, J=8.4), 7.60 (d, 2H, J=8.1), 7.45 (d, 2H,J=8.0), 7.34 (d, 2H, J=8.4), 7.10 (d, 2H, J=8.4), 6.93 (s, 1H), 6.83 (d,2H, J=8.4), 4.71 (s, 2H), 3.69 (t, 2H, J=7.2), 2.93 (t, 2H, J=7.3), 1.51(s, 6H). MS: m/z 575 (M+1).

2-(4-{2-[[2,4-Bis(trifluoromethyl)benzyl](4-tert-butyl-1,3-thiazol-2-yl)amino]ethyl}phenoxy)-2-methylpropanoicAcid

Similarly prepared from ethyl2-[4-(2-{(aminocarbonothioyl)[2,4-bis(trifluoromethyl)benzyl]amino}ethyl)phenoxy]-2-methylpropanoateand 1-bromopinacolone.

¹H NMR (CD₃OD) δ 7.96 (s, 1H), 7.85 (d, 1H, J=8.3), 7.59 (d, 1H, J=8.2),7.13 (d, 2H, J=8.4), 6.86 (d, 2H, J=8.4), 6.23 (s, ₁ H), 4.82 (s, 2H),3.72 (t, 2H, J=7.2), 3.00 (t, 2H, J=7.4), 1.56 (s, 6H), 1.22 (s, 9H).MS: m/z 589,(M+1).

2-[4-(2-{[2,4-Bis(trifluoromethyl)benzyl][4-(trifluoromethyl)-1,3-thiazol-2-yl]amino}ethyl)phenoxy]-2-methylpropanoicAcid

Similarly prepared from ethyl2-[4-(2-{(aminocarbonothioyl)[2,4-bis(trifluoromethyl)benzyl]amino}ethyl)phenoxy]-2-methylpropanoateand 3-bromo-1,1,1-trifluoroacetone.

¹H NMR (CD₃OD) δ 8.00 (s, 1H), 7.90 (d, 1H, J=8.1), 7.56 (d, 1H, J=8.3),7.15 (s, 1 H), 7.13 (d, 2H, J=8.3), 6.87 (d, 2H, J=8.4), 4.88 (s, 2H),3.79 (t, 2H, J=7.0), 3.01 (t, 2H, J=7.0), 1.56 (s, 6H). MS: m/z 601(M+1).

2-[4-(2-{[2,4-Bis(trifluoromethyl)benzyl][4-(2-chlorophenyl)-1,3-thiazol-2-yl]amino}ethyl)phenoxy]-2-methylpropanoicAcid

Similarly prepared from ethyl2-[4-(2-{(aminocarbonothioyl)[2,4-bis(trifluoromethyl)benzyl]amino}ethyl)phenoxy]-2-methylpropanoateand 2-chlorophenacyl bromide.

¹H NMR (CD₃OD) δ 7.95 (s, 1H), 7.86 (d, 1H, J=8.0), 7.76(d, 1H, J=8.1),7.60 (d, 1H, J=8.2), 7.47 (d, 1H, J=8.0), 7.31-7.25 (m, 2H), 7.11 (m,3H), 6.84 (d, 2H, J=8.3), 4.84 (s, 2H), 3.78 (t, 2H, J=7.0), 3.02 (t,2H, J=7.0), 1.52 (s, 6H).

2-[4-(2-{[2,4-Bis(trifluoromethyl)benzyl][4-(3,4-difluorophenyl)-1,3-thiazol-2-yl]amino}ethyl)phenoxy]-2-methylpropanoicAcid

Similarly prepared from ethyl2-[4-(2-{(aminocarbonothioyl)[2,4-bis(trifluoromethyl)benzyl]amino}ethyl)phenoxy]-2-methylpropanoateand 3,4-difluorophenacyl bromide.

¹H NMR (CD₃OD) δ 7.92 (s, 1H), 7.81 (d, 1H, J=8.0), 7.64-7.61 (m, 1H),7.54 (d, 1H, J=8.3), 7.37-7.28 (m, 2H), 7.12 (d, 2H, J=8.4), 6.96 (s,1H), 6.80 (d, 2H, J=8.3), 4.83 (s, 2H), 3.76 (t, 2H, J=7.2), 2.97 (t,2H, J=7.0), 1.48 (s, 6H).

2-[4-(2-{[2,4-Bis(trifluoromethyl)benzyl][4-(4-fluorophenyl)-1,3-thiazol-2-yl]amino}ethyl)phenoxy]-2-methylpropanoicAcid

Similarly prepared from ethyl2-[4-(2-{(aminocarbonothioyl)[2,4-bis(trifluoromethyl)benzyl]amino}ethyl)phenoxy]-2-methylpropanoateand 4-fluorophenacyl bromide.

¹H NMR (CD₃OD) δ 7.96 (s, 1H), 7.86-7.76 (m, 4H), 7.59 (d, 2H, J=8.2),7.13 (d, 2H, J=8.4), 7.05 (t, 2H, J=8.7), 6.91 (s, 1H), 6.84 (d, 2H,J=8.4), 4.87 (s, 2H), 3.78 (t, 2H, J=7.0), 3.01 (t, 2H, J=7.1), 1.52 (s,6H).

The following 9 compounds were prepared using similar procedures asthose described above.

2-[4-(2-{{4-[4-(diethylamino)phenyl]-1,3-thiazol-2-yl}[4-(trifluoromethyl)benzyl]amino}ethyl)phenoxy]-2-methylpropanoicAcid

2-methyl-2-[4-(2-{[4-(4-methylphenyl)-1,3-thiazol-2-yl][4-(trifluoromethyl)benzyl]amino}ethyl)phenoxy]propanoicAcid

2-[4-(2-{[2,4-bis(trifluoromethyl)benzyl][4-(3-chlorophenyl)-1,3-thiazol-2-yl]amino}ethyl)phenoxy]-2-methylpropanoicAcid

2-[4-(2-{[2,4-bis(trifluoromethyl)benzyl][4-(2-methoxyphenyl)-1,3-thiazol-2-yl]amino}ethyl)phenoxy]-2-methylpropanoicAcid

2-[4-(2-{[2,4-bis(trifluoromethyl)benzyl][4-(4-methylphenyl)-1,3-thiazol-2-yl]amino}ethyl)phenoxy]-2-methylpropanoicAcid

2-[4-(2-{[2,4-bis(trifluoromethyl)benzyl][4-(3-methoxyphenyl)-1,3-thiazol-2-yl]amino}ethyl)phenoxy]-2-methylpropanoicAcid

2-[4-(2-{[2,4-bis(trifluoromethyl)benzyl][4-(4-chlorophenyl)-1,3-thiazol-2-yl]amino}ethyl)phenoxy]-2-methylpropanoicAcid

2-[4-(2-{[2,4-bis(trifluoromethyl)benzyl][4-(4-propylphenyl)-1,3-thiazol-2-yl]amino}ethyl)phenoxy]-2-methylpropanoicAcid

2-[4-(2-{[4-(2-chlorophenyl)1,3-thiazol-2-yl][4-(trifluoromethoxy)benzyl]amino}ethyl)phenoxy]-2-methylpropanoicAcid

Binding Assay:

Compounds were tested for their ability to bind to hPPAR gamma,hPPARalpha or PPARdelta using a Scintillation Proximity Assay (SPA). ThePPAR ligand-binding domain (LBD) was expressed in E. coli as polyHistagged fusion proteins and purified. The LBD was then labeled withbiotin and immobilized on streptavidin-modified scintillation proximitybeads. The beads were then incubated with a constant amount of theappropriate radioligand (3H-BRL 49653 for PPARgamma, radiolabelled2-(4-(2-(2,3-Ditritio-1-heptyl-3-(2,4-difluorophenyl)ureido)ethyl)phenoxy)-2-methylbutanoicacid for hPPAR alpha (see WO 00/08002) and labelled GW 2433 (see Brown,P. J et al. Chem. Biol., 4, 909-918 (1997) for the structure andsynthesis of this ligand) for PPAR delta) and variable concentrations oftest compound, and after equilibration the radioactivity bound to thebeads was measured by a scintillation counter. The amount of nonspecificbinding, as assessed by control wells containing 50 μM of thecorresponding unlabeled ligand, was subtracted from each data point. Foreach compound tested, plots of ligand concentration vs. CPM ofradioligand bound were constructed and apparent KI values were estimatedfrom nonlinear least squares fit of the data assuming simple competitivebinding. The details of this assay have been reported elsewhere (see,Blanchard, S. G. et. al. Development of a Scintillation Proximity Assayfor Peroxisome Proliferator-Activated Receptor gamma Ligand BindingDomain. Anal. Biochem., 257, 112-119 (1998)).

Transfection Assay:

Compounds were screened for functional potency in transient transfectionassays in CV-1 cells for their ability to activate the PPAR subtypes(transactivation assay). A previously established chimeric receptorsystem was utilized to allow comparison of the relative transcriptionalactivity of the receptor subtypes on the same target gene and to preventendogenous receptor activation from complicating the interpretation ofresults. See, for example, Lehmann, J. M.; Moore, L. B.; Smith-Oliver,T. A.; Wilkison, W. O.; Willson, T. M.; Kliewer, S. A., An antidiabeticthiazolidinedione is a high affinity ligand for peroxisomeproliferator-activated receptor gamma (PPARgamma), J. Biol. Chem., 270,12953-6 (1995). The ligand binding domains for murine and human PPARalpha, PPAR gamma, and PPAR delta were each fused to the yeasttranscription factor GAL4 DNA binding domain. CV-1 cells weretransiently transfected with expression vectors for the respective PPARchimera along with a reporter construct containing five copies of theGAL4 DNA binding site driving expression of secreted placental alkalinephosphatase (SPAP) and beta-galactosidase. After 16 h, the medium wasexchanged to DME medium supplemented with 10% delipidated fetal calfserum and the test compound at the appropriate concentration. After anadditional 24h, cell extracts were prepared and assayed for alkalinephosphatase and beta-galactosidase activity. Alkaline phosphataseactivity was corrected for transfection efficiency using thebeta-galactosidase activity as an internal standard (see, for example,Kliewer, S. A., et. al. Cell 83, 813-819 (1995)). Rosiglitazone (BRL49653) was used as a positive control in the hPPAR gamma assay. Thepositive control for PPAR delta assays was2-{2-methyl-4-[({4-methyl-2-{trifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]phenoxy}aceticacid.

The positive control in the hPPARalpha transfection assay was2-[4-(2-(3-(4-fluorophenyl)-1-heptylureido)ethyl)-phenoxy]-2-methylpropionicacid, which can be prepared as described in Brown, Peter J., et. al.Synthesis Issue 7, 778-782 (1997), or patent publication WO 9736579.

All of the above exemplified compounds of this invention are agonists ofat least one hPPAR subtype as defined above on pages 5 and 6.

1. A compound of formula (1) or a pharmaceutically acceptable salt,solvate, acid isostere, or hydrolyzable ester thereof;

wherein R¹ and R² are independently hydrogen, F, CF₃, C₁₋₃alkyl, or R¹and R² may together with the carbon atom to which they are attached forma 3 to 6-membered cycloakyl ring; R⁴ and R⁵ are independently hydrogen,C₁₋₆alkyl, perfluoroC₁₋₆alkyl, —OC₁₋₃alkyl, perfluoroOC₁₋₆alkyl,halogen, or cyano; R⁷ and R⁸ are independently H, F, CF₃, or C₁₋₃alkyl,and the carbon to which R⁷ and R⁸ are bonded is attached to the benzenering either meta or para to the depicted oxygen; n is 1 or 2; y is 1 or2; R⁶ is phenyl or a 5- or 6-membered heteroaryl group, where the phenylor heteroaryl group is optionally substituted with 1, 2, or 3 moietiesselected from the group consisting of C₁₋₆alkyl, halogen,perfluoroC₁₋₃alkyl, OC₁₋₃alkyl, perfluoroOC₁₋₃alkyl, SC₁₋₃alkyl,SO₂C₁₋₃alkyl, SO₂C₁₋₃perfluoroalkyl, SOC₁₋₃perfluoroalkyl, SOC₁₋₃alkyl,perfluoroSC₁₋₃alkyl, CN, phenyl (optionally substituted with one or twogroups selected from halogen, C₁₋₃alkyl, OC₁₋₃alkyl, acetyl, CN, andperfluoroC₁₋₃alkyl), and 5- or 6-membered heteroaryl (optionallysubstituted with one group selected from C₁₋₃alkyl, C₃₋₆cycloalkyl,perfluoroC₁₋₃alkyl, NHC₁₋₃alkyl, and N(C₁₋₃alkyl)₂); and R³ is a 5- or6-membered heteroaryl group optionally substituted by 1 or 2 moietiesselected from the group consisting of halogen, C₁₋₆alkyl,perfluoroC₁₋₆alkyl, OC₁₋₃alkyl, phenyl (optionally substituted with oneor two moieties selected from C₁₋₃alkyl, halogen, OC₁₋₃alkyl, acetyl,CN, OperfluoroC₁₋₃alkyl, and perfluoroC₁₋₃alkyl), 5- or 6-memberedheteroaryl (optionally substituted with one or two moieties selectedfrom C₁₋₃alkyl, halogen, OC₁₋₃alkyl, acetyl, CN, andperfluoroC₁₋₃alkyl), hydroxyC₁₋₃alkyl, C₃₋₇cycloalkyl, cyanoC₁₋₃alkyl,acetyl, nitro, N(CH₃)₂, NHR²¹ (where R²¹ is C₁₋₃alkyl, —C(O)C₁₋₃alkyl,—C(O)OC₁₋₃alkyl, or SO₂CH₃), piperidin-4-yl (substituted at nitrogenwith a moiety selected from C₁₋₅alkyl, benzyl, acetyl, C(O)OC₁₋₅alkyl,C(O)Obenzyl, C(O)NH₂, C(O)NHC₁₋₃alkyl, SO₂CH₃),4-(4-fluorophenyl)piperazin-1-ylmethyl, morpholin-4-ylmethyl,tetrahydrofuran-3-yl, or two adjacent carbon atoms in the heteroarylcould be substituted to form a benzene ring thus forming a fused bicycleand wherein the resulting benzene ring is optionally substituted withone or two moieties selected from C₁₋₃alkyl, halogen, andperfluoroC₁₋₃alkyl.
 2. A compound of claim 1 wherein R¹ and R² areindependently hydrogen or C₁₋₃alkyl.
 3. A compound according to claim 1wherein R¹ and R² are both hydrogen or both methyl.
 4. A compoundaccording claim 2 wherein R⁴ and R⁵ are independently hydrogen,C₁₋₃alkyl, perfluoroC₁₋₃alkyl, —OC₁₋₃alkyl, perfluoroOC₁₋₃alkyl,halogen, or cyano.
 5. A compound according to claim 4 wherein at leastone of R⁴ and R⁵ are hydrogen
 6. A compound according to claim 5 whereinone of R⁴ and R⁵ is hydrogen and the other is not.
 7. A compoundaccording to claim 6 wherein the one of R⁴ and R⁵ that is not hydrogenis ortho to the depicted oxygen.
 8. A compound according claim 5 whereinR⁷ and R⁸ are independently hydrogen or methyl.
 9. A compound accordingto claim 5 R⁷ and R⁸ are both hydrogen or both methyl.
 10. A compoundaccording to claim 9 wherein y is
 1. 11. A compound according to claim10 wherein R⁶ is phenyl optionally substituted with 1 or 2 moietiesselected from the group consisting of F, Cl, CF₃, OCF₃, 5-memberednitrogen-containing heteroaryl (optionally substituted with one groupselected from C₁₋₃alkyl, C₃₋₆cycloalkyl, perfluoroC₁₋₃alkyl,NHC₁₋₃alkyl, and N(C₁₋₃alkyl)₂).
 12. A compound according to claim 11wherein R³ is selected from the group consisting of pyrimidine,pyridine, pyridazine, pyrazine, 1,2,4-oxadiazole, oxazole, and thiazole;and is optionally substituted by a moiety selected from the groupconsisting of halogen, C₁₋₆alkyl, perfluoroC₁₋₆alkyl, phenyl (optionallysubstituted with one or two moieties selected from C₁₋₃alkyl, halogen,OC₁₋₃alkyl, acetyl, CN, and perfluoroC₁₋₃alkyl), 5- or 6-memberedheteroaryl (optionally substituted with one or two moieties selectedfrom C₁₋₃alkyl, halogen, OC₁₋₃alkyl, acetyl, CN, andperfluoroC₁₋₃alkyl), hydroxyC₁₋₃alkyl, and C₃₋₇cycloalkyl, or R³ may besubstituted to form a fused bicycle selected from benzoxazole andbenzothiazole.
 13. A compound according to claim 12 wherein R³ is apyrimidine or a pyridine; and is optionally substituted by a moietyselected from the group consisting of halogen, C₁₋₆alkyl,perfluoroC₁₋₆alkyl, phenyl (optionally substituted with one or twomoieties selected from C₁₋₃alkyl, halogen, OC₁₋₃alkyl, acetyl, CN, andperfluoroC₁₋₃alkyl), 5- or 6-membered heteroaryl, hydroxyC₁₋₃alkyl, andC₃₋₇cycloalkyl.
 14. A compound according to claim 1 selected from thegroup consisting of:2-(4-{2-[[2,4-Bis(trifluoromethyl)benzyl](5-ethylpyrimidin-2-yl)amino]ethyl}phenoxy)-2-methylpropanoicacid;2-[4-(2-{(5-Ethylpyrimidin-2-yl)[4-(trifluoromethoxy)benzyl]amino}ethyl)phenoxy]-2-methylpropanoicacid;2-[4-2-{(5-Ethylpyrimidin-2-yl)[4-(trifluoromethyl)benzyl]amino}ethyl)phenoxy]-2-methylpropanoicacid;2-[4-(2-{(5-Ethylpyrimidin-2-yl)[4-(trifluoromethyl)benzyl]amino}ethyl)-2-methoxyphenoxy]-2-methylpropanoicacid;2-[2-Cyano-4-(2-{(5-ethylpyrimidin-2-yl)[4-(trifluoromethyl)benzyl]amino}ethyl)phenoxy]-2-methylpropanoicacid;2-[4-(2-{(5-Ethylpyrimidin-2-yl)[3-(trifluoromethoxy)benzyl]amino}ethyl)phenoxy]-2-methylpropanoicacid;2-[4-(2-{(5-Ethylpyrimidin-2-yl)[4-fluoro-2-(trifluoromethyl)benzyl]amino}ethyl)phenoxy]-2-methylpropanoicacid;2-[4-{2-[(4-chlorobenzyl)(5-ethylpyrimidin-2-yl)amino]ethyl}phenoxy]-2-methylpropanoicacid;2-[4-(2-{(5-Ethylpyrimidin-2-yl)[3-(trfluoromethyl)benzyl]amino}ethyl)phenoxy]-2-methylpropanoicacid;2-[4-{2-[(5-Ethylpyrimidin-2-yl)[4-fluorobenzyl]amino]ethyl}phenoxy]-2-methylpropanoicacid;[4-(2-{(5-Ethylpyrimidin-2-yl)[4-(trifluoromethyl)benzyl]amino}ethyl)phenoxy]aceticacid;2-[4-(2-{(5-Ethylpyrimidin-2-yl)[4-(5-isopropyl-1,2,4-oxadiazol-3-yl)benzyl]amino}ethyl)phenoxy]-2-methylpropanoicacid;[4-(2-{(5-Ethylpyrimidin-2-yl)[4-(trifluoromethoxy)benzyl]amino}ethyl)phenoxy]aceticacid;[4-(2-{(5-Ethylpyrimidin-2-yl)[4-(trifluoromethoxy)benzyl]amino}ethyl)-2-propylphenoxy]aceticacid;5-Ethyl-N-{2-[3-propyl-4-(2H-tetraazol-5-ylmethoxy)phenyl]ethyl}-N-[4-(trifluoromethoxy)benzyl]pyrimidin-2-amine;2-[4-(2(5-Ethylpyrimidin-2-yl)[4-(trifluoromethyl)benzyl]amino}-1,1-dimethylethyl)phenoxy]-2-methylpropanoicacid;2-[4-(2-{(5-ethylpyrimidin-2-yl)[4-(trifluoromethoxy)benzyl]amino}-1,1-dimethylethyl)phenoxy]-2-methylpropanoicacid;[4-(2-{(5-ethylpyrimidin-2-yl)[4-(trifluoromethoxy)benzyl]amino}-1,1-dimethylethyl)phenoxy]aceticacid;5-ethyl-N-{2-methyl-2-[4-(2H-tetraazol-5-ylmethoxy)phenyl]propyl}-N-[4-(trifluoromethoxy)benzyl]pyrimidin-2-amine;[2-Chloro-4-(2-{(5-ethylpyrimidin-2-yl)[4-(trifluoromethoxy)benzyl]amino}1,1-dimethylethyl)phenoxy]aceticacid;2-[2-Chloro-4-(2-{(5-ethylpyrimidin-2-yl)[4-(trifluoromethoxy)benzyl]amino}1,1-dimethylethyl)phenoxy]-2-methylpropanoicacid;2-[4-(2-{(5-Ethylpyrimidin-2-yl)[4-(trifluoromethoxy)benzyl]amino}1,1-dimethylethyl)2-propylphenoxy]-2-methylpropanoicacid;[4-(2-{(5-Ethylpyrimidin-2-yl)[4-(trifluoromethoxy)benzyl]amino}-1,1-dimethylethyl)-2-propylphenoxy]aceticacid;2-[4-(2{(5-Ethylpyrimidin-2-yl)[4-(trifluoromethoxy)benzyl]amino}ethyl)-2-methylphenoxy]-2-methylpropanoicacid;2-[2-Chloro-4-(2{(5-ethylpyrimidin-2-yl)[4-(trifluoromethoxy)benzyl]amino}ethyl)phenoxy]-2-methylpropanoicacid;2-[4-(2-{(5-Ethylpyrimidin-2-yl)[4-(trifluoromethoxy)benzyl]amino}ethyl)-2-(trifluoromethyl)phenoxy]-2-methylpropanoicacid;[4-(2-{(5-Ethylpyrimidin-2-yl)[4-(trifluoromethoxy)benzyl]amino}ethyl)-2-methylphenoxy]aceticacid;[4-(2-{(5-Ethylpyrimidin-2-yl)[4-(trifluoromethyl)benzyl]amino}ethyl)-2-fluorophenoxy]aceticacid ;[2-Chloro-4-(2-{(5-ethylpyrimidin-2-yl)[4-(trifluoromethoxy)benzyl]amino}ethyl)phenoxy]aceticacid;2-[4-(2{(5-Ethylpyridin-2-yl)[4-(trifluoromethyl)benzy]amino}ethyl)phenoxy]-2-methylpropanoicacid;2-[4-(2{(5-Ethylpyridin-2-yl)[4-(trifluoromethoxy)benzyl]amino}ethyl)phenoxy]-2-methylpropanoicacid;2-[4-(2-{(5-Isopropylpyrdin-2-yl)[4-(trifluoromethyl)benzyl]amino}ethyl)phenoxy]-2-methylpropanoicacid;2-[4-(2-{(5-Isopropylpyridin-2-yl)[4-(trifluoromethoxy)benzyl]amino}ethyl)phenoxy]-2-methylpropanoicacid;2-Methyl-2-[4-(2-{[5-(2,2,2-trifluoroethyl)pyridin-2-yl][4-(trifluoromethoxy)benzyl]amino}ethyl)phenoxy]propanoicacid;2-[4-(2-{[5-(Hydroxymethyl)pyridin-2-yl][4-(trifluoromethoxy)benzyl]amino}ethyl)phenoxy]-2-methylpropanoicacid;2-[4-(3{(5-Isopropylpyridin-2-yl)[4-(trifluoromethoxy)benzyl]amino}propyl)phenoxy]-2-methylpropanoicacid;2-[4-(2-{[4-(2-Chlorophenyl)-1,3-thiazol-2-yl][4-(trifluoromethyl)benzyl]amino}ethyl)phenoxy]-2-methylpropanoicacid;2-[4-(2-{[4-(3,4-Difluorophenyl)-1,3-thiazol-2-yl][4-(trifluoromethyl)benzyl]amino}ethyl)phenoxy]-2-methylpropanoicacid; and pharmaceutically acceptable salts, solvates, acid isosteres,and hydrolyzable esters thereof.
 15. A compound according to claim 1selected from the group consisting of:2-[4-(2{(5-ethylpyrimidin-2-yl)[4-(trifluoromethoxy)benzyl]amino}-1,1-dimethylethyl)phenoxy]-2-methylpropanoicacid,2-[4-(2-{[4-(2-Chlorophenyl)-1,3-thiazol-2-yl][4-(trifluoromethyl)benzyl]amino}ethyl)phenoxy]-2-methylpropanoicacid,2-[4-(2-{[4-(3,4-Difluorophenyl)-1,3-thiazol-2-yl][4-(trifluoromethyl)benzyl]amino}ethyl)phenoxy]-2-methylpropanoicacid, and pharmaceutically acceptable salts, solvates, acid isosteres,and hydrolyzable esters thereof.
 16. A compound of according to claim 1wherein R¹ and R₂ are both hydrogen or both methyl; at least one of R⁴and R⁵ are hydrogen; R⁷ and R⁸ are both hydrogen or both methyl; y is 1;R⁶ is phenyl optionally substituted with 1 or 2 moieties selected fromthe group consisting of F, Cl, CF₃, OCF₃, 5-membered nitrogen-containingheteroaryl (optionally substituted with one group selected fromC₁₋₃alkyl, C₃₋₆cycloalkyl, perfluoroC₁₋₃alkyl, NHC₁₋₃alkyl, andN(C₁₋₃alkyl)₂); and R³ is a thiazole, a pyrimidine, or a pyridine and isoptionally substituted by a moiety selected from the group consisting ofhalogen, C₁₋₆alkyl, perfluoroC₁₋₆alkyl, phenyl (optionally substitutedwith one or two moieties selected from C₁₋₃alkyl, halogen, OC₁₋₃alkyl,acetyl, CN, and perfluoroC₁₋₃alkyl), 5- or 6-membered heteroaryl,hydroxyC₁₋₃alkyl, and C₃₋₇cycloalkyl.
 17. A compound according to claim1 wherein the compound is a hPPAR agonist.
 18. A method for preventionor treatment of a disease or condition associated with one or more ofhuman PPAR alpha, gamma, or delta (“hPPARs”) comprising administrationof a therapeutically effective amount of a compound of claim
 17. 19. Themethod of claim 18 wherein said disease or condition is selected fromthe group consisting of dyslipidemia including associated diabeticdyslipidemia and mixed dyslipidemia, syndrome X, heart failure,hypercholesteremia, cardiovascular disease including atherosclerosis,arteriosclerosis, and hypertriglyceridemia, type II diabetes mellitus,type I diabetes, insulin resistance, hyperlipidemia, inflammation,epithelial hyperproliferative diseases including eczema and psoriasisand conditions associated with the lung and gut and regulation ofappetite and food intake in subjects suffering from disorders such asobesity, anorexia bulimia, and anorexia nervosa.
 20. The method of claim18 wherein said disease or condition is selected from the groupconsisting of diabetes and cardiovascular diseases and conditionsincluding atherosclerosis, arteriosclerosis, hypertriglyceridemia, andmixed dyslipidemia.
 21. A pharmaceutical composition comprising acompound according to claim
 1. 22-23. (canceled)